Substituted 4-Amino-Pyrrolotriazine Derivatives Useful for Treating Hyper-Proliferative Disorders and Diseases Associated with Angiogenesis

ABSTRACT

This invention relates to novel pyrrozolotriazine compounds, pharmaceutical compositions containing such compounds and and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.

FIELD OF THE INVENTION

This invention relates to novel pyrrozolotriazine compounds,pharmaceutical compositions containing such compounds and and the use ofthose compounds or compositions for treating hyper-proliferative and/orangiogenesis disorders, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

Cancer is a disease resulting from an abnormal growth of tissue. Certaincancers have the potential to invade into local tissues and alsometastasize to distant organs. This disease can develop in a widevariety of different organs, tissues and cell types. Therefore, the term“cancer” refers to a collection of over a thousand different diseases.

Over 4.4 million people worldwide were diagnosed with breast, colon,ovarian, lung, or prostate cancer in 2002 and over 2.5 million peopledied of these devastating diseases (Globocan 2002 Report). In the UnitedStates alone, over 1.25 million new cases and over 500,000 deaths fromcancer were predicted in 2005. The majority of these new cases wereexpected to be cancers of the colon (˜100,000), lung (˜170,000), breast(˜210,000) and prostate (˜230,000). Both the incidence and prevalence ofcancer is predicted to increase by approximately 15% over the next tenyears, reflecting an average growth rate of 1.4% (American CancerSociety, Cancer Facts and Figures 2005).

Cancer treatments are of two major -types, either curative orpalliative. The main curative therapies for cancer are surgery andradiation. These options are generally successful only if the cancer isfound at an early localized stage (Gibbs J B, 2000). Once the diseasehas progressed to locally advanced cancer or metastatic cancer, thesetherapies are less effective and the goal of therapy aims at symptompalliation and maintaining good quality of life.

The most prevalent treatment protocols in either treatment mode involvea combination of surgery, radiation therapy and/or chemotherapy.

Cytotoxic drugs (also known as cytoreductive agents) are used in thetreatment of cancer, either as a curative treatment or with the aim ofprolonging life or palliating symptoms. Cytotoxics may be combined withradiotherapy and/or surgery, as neo-adjuvant treatment (initialchemotherapy aimed at shrinking the tumor, thereby rendering localtherapy such as surgery and radiation more effective) or as adjuvantchemotherapy (used in conjunction or after surgery and/or localizedtherapy). Combinations of different drugs are frequently more effectivethan single drugs: they may provide an advantage in certain tumors ofenhanced response, reduced development of drug resistance and/orincreased survival. It is for these reasons that the use of combinedcytotoxic regimens in the treatment of many cancers is very common.

Cytotoxic agents in current use employ different mechanisms to blockproliferation and induce cell death. They can be generally categorizedinto the following groups based on their mechanism of action: themicrotubule modulators that interfere with the polymerization ordepolymerization of mnicrotubules (e.g. docetaxel, paclitaxel,vinblastine, vinorelbine); anti-metabolites including nucleoside analogsand other inhibitors of key cellular metabolic pathways (e.g.capecitabine, gemcitabine, methotrexate); agents that interact directlywith DNA (e.g. carboplatin, cyclophosphamide); anthracycline DNAinterchalators that interfere with DNA polymerase and Topoisomerase II(e.g. doxorubicin, epirubicin); and the non-anthracycline inhibitors ofTopoisomerase II and I enzymatic activity (e.g. topotecan, irinotecan,and etoposide). Even though different cytotoxic drugs act via differentmechanisms of action, each generally leads to at least transientshrinkage of tumors.

Cytotoxic agents continue to represent an important component in anoncologist's arsenal of weapons for use in fighting cancer. The majorityof drugs currently undergoing late Phase II and Phase III clinicaltrials are focusing on known mechanisms of action (tubulin bindingagents, anti-metabolites, DNA processing), and on incrementalimprovements in known drug classes (for example the taxanes or thecamptothecins). A small number of cytotoxic drugs based on novelmechanisms have recently emerged. Modes of action for these cytotoxicsinclude inhibition of enzymes involved in DNA modification [e.g. histonedeacetylase (HDAC)], inhibition of proteins involved in microtubulemovement and cell cycle progression (e.g. kinesins, aurora kinase), andnovel inducers of the apoptotic pathway (e.g. bcl-2 inhibitors).

The link between activity in tumor cell proliferation assays in vitroand anti-tumor activity in the clinical setting has been wellestablished in the art. For example, the therapeutic utility of taxol(Silvestrini et al. Stem Cells 1993, 11(6), 528-35), taxotere (Bisseryet al. Anti Cancer Drugs 1995, 6(3), 339), and topoisomerase inhibitors(Edelman et al. Cancer Chemother.

Cells protect their DNA by adopting a higher-order complex termedchromatin. Chromatin condensation is evident during mitosis and celldeath induced by apoptosis while chromatin. decondensation is necessaryfor replication, repair, recombination and transcription. Histones areamong some of the DNA-binding proteins that are involved in theregulation of DNA condensation; and post-translational modifications ofhistone tails serve a critical role in the dynamiccondensation/decondensation that occurs during the cell cycle.Phoshorylation of the tails of histone H3 is involved in bothtranscription and cell division (Prigent et al. J. Cell Science 2003,116, 3677). A number of protein kinases have been reported tophosphorylate histone H3 and these kinases function both as signaltransduction and mitotic kinases.

Even though cytotoxic agents remain in the forefront of approaches totreat patients with advanced solid tumors, their limited efficacy andnarrow therapeutic indices result in significant side effects. Moreover,basic research into cancer has led to the investigation of less toxictherapies based on the specific mechanisms central to tumor progression.Such studies could lead to effective therapy with improvement of thequality of life for cancer patients. Thus, a new class of therapeuticagents has emerged, referred to as cytostatics. Cytostatics direct theiraction on tumor stabilization and are generally associated with a morelimited and less aggravating side effect profile. Their development hasresulted from the identification of specific genetic changes involved incancer progression and an understanding of the proteins activated incancer such as tyrosine kinases and serine/threonine kinases.

In addition to direct inhibition of tumor cell targets, cytostatic drugsare being developed to block the process of tumor angiogenesis. Thisprocess supplies the tumor with existing and new blood vessels tosupport continued nourishment and therefore help promote tumor growth.Key tyrosine kinase receptors including Vascular Endothelial GrowthFactor Receptor 2 (VEGFR2), Fibroblast Growth Factor 1 (FGFR1) and Tie2have been shown to regulate angiogenesis and have emerged as highlyattractive drug targets.

To support progressive tumor growth beyond the size of 1-2 mm³, it isrecognized that tumor cells require a functional stroma, a supportstructure consisting of fibroblast, smooth muscle cells, endothelialcells, extracellular matrix proteins, and soluble factors (Folkman, J.,Semin Oncol, 2002. 29(6 Suppl 16), 15-8). Tumors induce the formation ofstromal tissues through the secretion of soluble growth factors such asPDGF and transforming growth factor-beta (TGF-beta), which in turnstimulate the secretion of complimentary factors by host cells such asfibroblast growth factor (FGF), epidermal growth factor (EGF), andvascular endothelial growth factor (VEGF). These stimulatory factorsinduce the formation of new blood vessels, or angiogenesis, which bringsoxygen and nutrients to the tumor and allows it to grow and provides aroute for metastasis. It is believed some therapies directed atinhibiting stroma formation will inhibit the growth of epithelial tumorsfrom a wide variety of histological types. (George, D. Semin Oncol,2001. 28(5 Suppl 17), 27-33; Shaheen, R. M., et al., Cancer Res, 2001.61(4), 1464-8; Shaheen, R. M., et al. Cancer Res, 1999. 59(21), 5412-6).However, because of the complex nature and the multiple growth factorsinvolved in angiogenesis process and tumor progression, an agenttargeting a single pathway may have limited efficacy. It is desirable toprovide treatment against a number of key signaling pathways utilized bytumors to induce angiogenesis in the host stroma. These include PDGF, apotent stimulator of stroma formation (Ostman, A. and C. H. Heldin, AdvCancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen forfibroblasts and endothelial cells, and VEGF, a potent regulator ofvascularization.

A major regulator of angiogenesis and vasculogenesis in both embryonicdevelopment and some angiogenic-dependent diseases is vascularendothelial growth factor (VEGF; also called vascular permeabilityfactor, VPF). VEGF represents a family of isoforms of mitogens existingin homodimeric forms due to alternative RNA splicing. The VEGF isoformsare reported to be highly specific for vascular endothelial cells (forreviews, see: Parrara et al. Endocr. Rev. 1992, 13, 18; Neufieldet al.FASEB J. 1999, 13, 9).

VEGF expression is reported to be induced by hypoxia (Shweiki et al.Nature 1992, 359, 843), as well as by a variety of cytokines and growthfactors, such as interleukin-1, interleukin-6, epidermal growth factorand transforming growth factor. To date, VEGF and the VEGF familymembers have been reported to bind to one or more of three transmembranereceptor tyrosine kinases (Mustonen et al. J. Cell Biol., 1995, 129,895), VEGF receptor-1 (also known as flt-1 (fns-like tyrosinekinase-1)), VEGFR-2 (also known as kinase insert domain containingreceptor (KDR); the murine analogue of KDR is known as fetal liverkinase-1 (flk-1)), and VEGFR-3 (also known as flt-4). KDR and flt-1 havebeen shown to have different signal transduction -properties(Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al.Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependanttyrosine phosphorylation in intact cells, whereas flt-1 displays a weakresponse. Thus, binding to KDR is believed to be a critical requirementfor induction of the full spectrum of VEGF-mediated biologicalresponses.

In vivo, VEGF plays a central role in vasculogenesis, and inducesangiogenesis and permeabilization of blood vessels. Deregulated VEGFexpression contributes to the development of a number of diseases thatare characterized by abnormal angiogenesis and/or hyperpermeabilityprocesses. It is believed regulation of the VEGF-mediated signaltransduction cascade by some agents can provide a useful mode forcontrol of abnormal angiogenesis and/or hyperpermeability processes.

The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and theirreceptors (VEGFR2, VEGFR3) are not only key regulators of tumorangiogenesis, but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D areexpressed in most tumors, primarily during periods of tumor growth and,often at substantially increased levels. VEGF expression is stimulatedby hypoxia, cytokines, oncogenes such as ras, or by inactivation oftumor suppressor genes (McMahon, G. Oncologist 2000, 5(Suppl. 1), 3-10;McDonald, N. Q.; Hendrickson, W. A. Cell 1993, 73, 421-424).

The biological activities of the VEGFs are mediated through binding totheir receptors. VEGFR3 (also called Flt4) is predominantly expressed onlymphatic endothelium in normal adult tissues. VEGFR3 function is neededfor new lymphatic vessel formation, but not for maintenance of thepre-existing lymphatics. VEGFR3 is also upregulated on blood vesselendothelium in tumors. Recently VEGF-C and VEGF-D, ligands for VEGFR3,have been identified as regulators of lymphangiogenesis in mammals.Lymphangiogenesis induced by tumor-associated lymphangiogenic factorscould promote the growth of new vessels into the tumor, providing tumorcells access to systemic circulation. Cells that invade the lymphaticscould find their way into the bloodstream via the thoracic duct. Tumorexpression studies have allowed a direct comparison of VEGF-C, VEGF-Dand VEGFR3 expression with clinicopathological factors that relatedirectly to the ability of primary tumors to spread (e.g., lymph nodeinvolvement, lymphatic invasion, secondary metastases, and disease-freesurvival). In many instances, these studies demonstrate a statisticalcorrelation between the expression of lymphangiogenic factors and theability of a primary solid tumor to metastasize (Skobe, M. et al. NatureMed. 2001, 7(2), 192-198; Stacker, S. A. et al. Nature Med. 2001, 7(2),186-191; Makinen, T. et al. Nature Med. 2001, 7(2), 199-205; Mandriota,S. J. et al. EMBO J. 2001, 20(4), 672-82; Karpanen, T. et al. CancerRes. 2001, 61(5), 1786-90; Kubo, H. et al. Blood 2000, 96(2), 546-53).

Hypoxia appears to be an important stimulus for VEGF production inmalignant cells. Activation of p38 MAP kinase is required for VEGFinduction by tumor cells in response to hypoxia (Blaschke, F. et al.Biochem Biophys. Res. Commun. 2002, 296, 890-896; Shemirani, B. et al.Oral Oncology 2002, 38, 251-257). In addition to its involvement inangiogenesis through regulation of VEGF secretion, p38 MAP kinasepromotes malignant cell invasion, and migration of different tumor typesthrough regulation of collagenase activity and urokinase plasminogenactivator expression (Laferriere, J. et al. J. Biol. Chem. 2001, 276,33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162;Huang, S. et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al.Exp. Cell Res. 2001, 271, 344-355). Moreover, VEGF activates theextracellular signal-regulated protein kinase (ERK) in human umbilicalvein endothelial cells (HUVEC) (Yu, Y.; Sato, D. J. Cell Physiol 1999,178, 235-246).

The VEGF-VEGFR2 signaling pathway has been extensively characterized asan important regulator of angiogenesis. Mice lacking VEGFR2 (Flk-1) arealmost completely lacking in vasculature and have very few endothelialcells (Shalaby et al., Nature, 1995, 376, 62-66). VEGF is a potentmitogen for endothelial cells, promotes angiogenic sprouting, andincreases vascular permeability (reviewed in Yancopoulos et al. Nature2000, 407, 242). Administration of soluble VEGFR2 inhibits the growth ofwide variety of tumors (Shirakawa et al. Int J Cancer, 2002, 99, 244,Bruns et al. Cancer, 2000, 89, 495, Millauer et al., Nature 1994, 367,576). Similarly, neutralizing antibodies to VEGF (Kim et al., Nature,1993, 262, 841) or VEGFR2 (Prewett et al., Cancer Res 1999, 59, 5209),as well as VEGF antisense (Saleh et al. Cancer Res 1996, 56, 393)suppress tumor growth in vivo. Furthermore, small molecule inhibitors ofVEGFR2 have been shown to inhibit tumor growth in preclinical xenograftmodels (reviewed in Shepherd and Sridhar, Lung Cancer, 2003, 41, S63)and are being tested in clinical trials. A monoclonal antibody to VEGF(Avastin™) was recently approved for use in combination with otheranticancer drugs for treatment of advanced colon cancer.

The Ang-Tie2 signal transduction pathway also plays a key role invascular formation, particularly with respect to remodeling andstabilization of vessels. The major ligands for Tie2, Angiopoietin-1 andAngiopoietin-2 (Ang1 and Ang2), have distinct activities. While Ang1 isa Tie2 agonist, promoting vessel maturation and stability, Ang2 ispartial Tie2 agonist/antagonist having varied activities that aredependent on the tissue and growth factor context (Yancopoulos et al.Nature, 2000, 407, 242). When the local concentration of VEGF is low,Ang2 promotes vessel regression, whereas in areas where VEGFconcentrations are high, Ang2 induces vessel destabilization andbranching (Holash et al. Ocogene, 1999, 18, 5356). This latter situationis likely the case during active tumor angiogenesis. Ang1 has been shownto regulate endothelial cell survival (Kwak et al. FEBS, 1999, 448, 249,Bussolati et al. FEBS, 2003, 9, 1159) and migration (Witzenbichler etal. J. Biol Chem, 1998, 373, 18514). The role of Ang-Tie2 signaling intumor angiogenesis is supported by numerous xenograft tumor studiesinvolving the administration of soluble Tie2. Significant inhibition oftumor growth by soluble Tie2 was observed in the WIBC-9 and MC-5 humanbreast tumors (Shirakawa et al. Int J Cancer, 2002, 99, 344), C26 colonand TS/A breast tumors, R3230AC breast tumor (Lin et al. J Clin Invest,1997, 100, 2072), A375v melanoma (Siemeister et al. Cancer Res, 1999,59, 3185), as well as 4T1 murine mammary and B 16F10.9 murine melanomatumors.

The central role of the FGF-FGFR1 signal transduction pathway inangiogenesis is well established. The FGF family includes 22 membersexpressed from different genes and having distinct activities (Ornitzand Itoh, Genome Biology, 2001, 2, reviews 3005). During mammaliandevelopment, FGF1 and FGF2 regulate branching morphogenesis in tissuesundergoing vascularization. Administration of FGFs can promoteneovascularization in ischemic tissues (Yanagisawa-Miwa et al., Science,1992, 257, 1401, Tabata et al. Cardiovasc Res, 1997, 35, 470.). FGFR1binds FGF1 and FGF2 with similar affinity (Dionne et al., EMBO J, 1990,9, 2685). The FGF-FGFR1 pathway has also been associated withangiogenesis in a variety of tumor types. FGF2 is a key regulator ofangiogenesis in prostate cancer (Doll et al. Prostate, 2001, 49, 293)and melanomas (Straume and Akslen Am J Pathol, 2002, 160, 1009). Inaddition, antisense targeting of FGFR1 (Wang and Becker Nat Med, 1997,3, 887) or anti-FGF2 antibodies (Rofstad and Halsor Cancer Res, 2000,60, 4932) inhibit tumor growth and angiogenesis in human melanomas.Similarly, expression of soluble FGFR decreases the growth ofspontaneous pancreatic tumors in mice (Compagni et al. Cancer Res, 2000,60, 7163), as well as xenografted pancreatic tumors (Wagner et al.Gastroenterology, 1998, 114, 798). Overexpression and amplification ofthe FGFR1 gene in human breast tumors (Jacquemier et al. Int J Cancer,1994, 59, 373) and bladder cancers (Simon et al. Cancer Res, 2001, 61,4514), has been reported whereas translocation of FGFR1 resulting in anactivated chimeric kinase has been identified in myeloproliferativedisorders with lymphoma (Gausch et al. Mol Cell Biol 2001, 21, 8129) andChronic Myelogenous Leukemias (CML, Demiroglu et al., Blood, 2001, 98,3778).

The activation of FGFR1 by FGF induces both the MAPK/ERK and thePI3K/Akt pathways. In contrast to Ang1, which is not a mitogen, FGFstimulates cell proliferation via the MAPK/ERK pathway (Bikfalvi et al.,Endocr Rev, 1997, 18, 26). Activation of FGFR1 leads to the recruitmentof adaptor proteins FRS2 and GRB2, which recruit SOS to the plasmamembrane leading to the activation of RAS (Kouhara et al., Cell, 1997,89, 693). Activated RAS, which subsequently activates RAF, MEK, thenERK, leads to cell proliferation. The activation of p38 MAPK has alsobeen reported to be involved in FGF-induced cell proliferation. (Maher,J Biol Chem, 1999, 274,17491). The recruitment of GRB2 to activatedFGFR1 also recruits Gabl, which induces the PI3K/Akt pathway (Ong etal., Mol Cell Biol, 2000, 20, 979), and promotes cell survival. Thiseffect of Akt on cell survival is mediated, in part through mTOR andp70^(S6K) (Gausch et al., Mol Cell, Biol, 2001, 21, 8129). The effectsof FGF on cell migration have been shown to be mediated, in part, by ERKactivation and c-Fes (reviewed in Javerzat et al., Trends in MolecularMedicine, 2002, 8, 483).

PDGF is another key regulator of stromal formation which is secreted bymany tumors in a paracrine fashion and is believed to promote the growthof fibroblasts, smooth muscle and endothelial cells, promoting stromaformation and angiogenesis. PDGF was originally identified as the v-sisoncogene product of the simian sarcoma virus (Heldin, C. H., et al., JCell Sci Suppl, 1985, 3, 65-76). The growth factor is made up of twopeptide chains, referred to as A or B chains which share 60% homology intheir primary amino acid sequence. The chains are disulfide cross linkedto form the 30 kDa mature protein composed of either AA, BB or AB homo-or heterodimmners. PDGF is found at high levels in platelets, and isexpressed by endothelial cells and vascular smooth muscle cells. Inaddition, the production of PDGF is up regulated under low oxygenconditions such as those found in poorly vascularized tumor tissue(Kourembanas, S., et al., Kidney Int, 1997, 51(2), 438-43). PDGF bindswith high affinity to the PDGF receptor, a 1106 amino acid 124 kDatransmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L.Ronnstrand, Biochim Biophlys Acta, 1998. 1378(1), 79-113). PDGFR isfound as homo- or heterodimer chains which have 30% homology overall intheir amin6 acid sequence and 64% homology between their kinase domains(Heldin, C. H., et al. Embo J, 1988, 7(5), 1387-93). PDGFR is a memberof a family of tyrosine kinase receptors with split kinase domains thatincludes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3. The PDGF receptoris expressed primarily on fibroblast, smooth muscle cells, and pericytesand to a lesser extent on neurons, kidney mesangial, Leydig, and Schwanncells of the central nervous system. Upon binding to the receptor, PDGFinduces receptor dimerization and undergoes auto- andtrans-phosphorylation of tyrosine residues which increase the receptors'kinase activity and promotes the recruitment of downstream effectorsthrough the activation of SH2 protein binding domains. A number ofsignaling molecules form complexes with activated PDGFR includingPI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activatingprotein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38(6),1757-64). Through the activation of PI-3-kinase, PDGF activates the Rhosignaling pathway inducing cell motility and migration, and through theactivation of GAP, induces mitogenesis through the activation of p21-rasand the MAPK signaling pathway.

In adults, it is believed the major function of PDGF is to facilitateand increase the rate of wound healing and to maintain blood vesselhomeostasis (Baker, E. A. and D. J. Leaper, Wound Repair Regen, 2000.8(5), 392-8; Yu, J., A. Moon, and H. R. Kim, Biochem Biophys Res Commun,2001. 282(3), 697-700). PDGF is found at high concentrations inplatelets and is a potent chemoattractant for fibroblast, smooth musclecells, neutrophils and macrophages. In addition to its role in woundhealing PDGF is known to help maintain vascular homeostasis. During thedevelopment of new blood vessels, PDGF recruits pericytes and smoothmuscle cells that are needed for the structural integrity of thevessels. PDGF is thought to play a similar role during tumorneovascularization. As part of its role in angiogenesis PDGF controlsinterstitial fluid pressure, regulating the permeability of vesselsthrough its regulation of the interaction between connective tissuecells and the extracellular matrix. Inhibiting PDGFR activity can lowerinterstitial pressure and facilitate the influx of cytotoxics intotumors improving the anti-tumor efficacy of these agents (Pietras, K.,et al. Cancer Res, 2002. 62(19), 5476-84; Pietras, K., et al. CancerRes, 2001. 61(7), 2929-34).

PDGF can promote tumor growth through either the paracrine or autocrinestimulation of PDGFR receptors on stromal cells or tumor cells directly,or through the amplification of the receptor or activation of thereceptor by recombination. Over expressed PDGF can transform humanmelanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl AcadSci USA., 1993. 90(2), 393-7; Skobe, M. and N. E. Fusenig, Proc NatlAcad Sci USA, 1998. 95(3), 1050-5), two cell types that do not expressPDGF receptors, presumably by the direct effect of PDGF on stromaformation and induction of angiogenesis. This paracrine stimulation oftumor stroma is also observed in carcinomas of the colon, lung, breast,and prostate (Bhardwaj, B., et al. Clin Cancer Res, 1996, 2(4), 773-82;Nakanishi, K., et al. Mod Pathol, 1997, 10(4), 341-7; Sundberg, C., etal. Am J Pathol, 1997, 151(2), 479-92; Lindmark, G., et al. Lab Invest,1993, 69(6), 682-9; Vignaud, J. M., et al., Cancer Res, 1994, 54(20),5455-63) where the tumors express PDGF, but not the receptor. Theautocrine stimulation of tumor cell growth, where a large faction oftumors analyzed express both the ligand PDGF and the receptor, has beenreported in glioblastomas (Fleming, T. P., et al. Cancer Res, 1992,52(16), 4550-3), soft tissue sarcomas (Wang, J., M. D. Coltrera, and A.M. Gown, Cancer Res, 1994, 54(2), 560-4) and cancers of the ovary(Henriksen, R., et al. Cancer Res, 1993, 53(19), 4550-4), prostate(Fudge, K., C. Y. Wang, and M. E. Stearns, Mod Pathol, 1994, 7(5),549-54), pancreas (Funa, K., et al. Cancer Res, 1990, 50(3), 748-53) andlung (Antoniades, H. N., et al., Proc Natl Acad Sci USA, 1992, 89(9),3942-6). Ligand independent activation of the receptor is found to alesser extent but has been reported in chronic myelomonocytic leukemia(CMML) where the a chromosomal translocation event forms a fusionprotein between the Ets-like transcription factor TEL and the PDGFreceptor. In addition, activating mutations in PDGFR have been found ingastrointestinal stromal tumors in which c-Kit activation is notinvolved (Heinrich, M. C., et al., Science, 2003, 9, 9). Certain PDGFRinhibitors will interfere with tumor stromal development and arebelieved to inhibit tumor growth and metastasis.

Several new drugs that are directed at various molecular targets havebeen approved over the past several years for the treatment of cancer.Imatinib is an inhibitor of the Abl tyrosine kinase and was the firstsmall molecule tyrosine kinase inhibitor to be approved for thetreatment of chronic myeloid leukemia (CML). Based on additionalactivity of imatinib against the receptor tyrosine kinase activated ingastrointestinal stromal tumors (GIST), c-KIT, it was subsequentlyapproved for the treatment of advanced GIST. Erlotinib, a small moleculeinhibitor of EGFR, was approved in late 2004 for the treatment ofnon-small cell lung carcinoma (NSCLC). Sorafenib, an inhibitor ofmultiple kinases including c-Raf and VEGFR2 was approved for thetreatment of advanced renal cell carcinoma (RCC) in December, 2005.Recently in January of 2006, Sunitinib, a multi-kinase inhibitor wasapproved for the treatment of refractory- or resistant-GIST and advancedRCC. These small molecule inhibitors demonstrate that targetedapproaches are successful for the treatment of different types ofcancers.

Despite advancements in the art, there remains a need for cancertreatments and anti-cancer compounds.

Compounds and compositions described herein, including salts,metabolites, solvates, solvates of salts, hydrates, prodrugs such asesters, polymorphs, and stereoisomeric forms thereof, exhibitanti-proliferative and anti-angiogenic activity and are thus useful toprevent or treat the disorders associated with hyper-proliferation andangiogenesis.

DESCRIPTION OF THE INVENTION

In embodiment one, the present invention provides a compound of formula(I)

-   wherein-   X⁰ represents C or N;-   R¹ represents    -   1.1) phenyl or a bicyclic carbocycle of 9-10 ring members, in        which at least one ring is aromatic, R¹ optionally bearing up to        4 substituents independently selected from the group consisting        of        -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.1.a1) halogen;            -   1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or                —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(7a) wherein R^(7a) represents H or (C₁-C₃)alkyl, or                R⁶ and R⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -   1.1.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.1.b1) halogen; and            -   1.1.b2) OR⁹ wherein R⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or (C₁-C₃)mono- or                di-alkylamino;        -   1.1.c) OR¹⁰ wherein            -   R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.1.c1) halogen;            -   1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -   1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;        -   1.1.d) —C(O)—OR¹⁵ wherein R¹⁵ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;        -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -   R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.1.e1) halogen;            -   1.1.e2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.1.e3) phenyl;            -   1.1.e4) —SO₂CH₃;            -   1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;        -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -   R²² represents H or (C₁-C₃)alkyl; and            -   R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.1.f1) optionally substituted phenyl,            -   1.1.f2) OR²⁴ wherein R²⁴ represents H or (C₁-C₃)alkyl,                or            -   1.1.f3) NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R²⁵ and R²⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²⁷ wherein R²⁷ represents H or (C₁-C₃)alkyl;        -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -   R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -   1.1.g1) halogen;            -   1.1.g2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.1.g3) phenyl;            -   1.1.g4) —SO₂CH₃;            -   1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;        -   1.1.h) —N(R⁷)—SO₂—R³⁵ wherein            -   R³⁴ represents H or (C₁-C₃)alkyl, and            -   R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.1.h1) halogen;            -   1.1.h2) optionally substituted phenyl,            -   1.1.h3) OR³⁶ wherein R³⁶ represents H or (C₁-C₃)alkyl,                or            -   1.1.h4) NR³⁷R³⁸ wherein R³⁷ and R³⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³⁷ and R³⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³⁹ wherein R³⁹ represents H or (C₁-C₃)alkyl;        -   1.1.i) —NR⁴¹R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in            which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may            be joined and taken together with the N atom to which they            are attached form a 5-6 membered ring which may optionally            contain a ring member selected from O, S, and NR⁴³ wherein            R⁴³ represents H or (C₁-C₃)alkyl;        -   1.1.j) halogen;        -   1.1.k) optionally substituted phenyl;        -   1.1.1) NO₂;        -   1.1.m) CN; and        -   1.1.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;        -   1.1.o) —C(O)—R²⁹ wherein R²⁹ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   or-   R¹ represents    -   1.2) a 5-6 membered aromatic heterocycle containing up to 3        heteroatoms independently selected from the group consisting of        N, O, and S; or a bicyclic heterocycle of 8-10 ring members in        which at least one ring is aromatic and contains up to 3        moieties independently selected from the group consisting of N,        N→O, O, and S, and any non-aromatic ring of said bicyclic        heterocycle optionally contains up to three moieties        independently selected from the group consisting of O, S, S(O),        S(O)₂, and NR⁴⁴ wherein R⁴⁴ represents H or —(C₁-C₃)alkyl; said        R¹ heterocycle optionally bearing up to 4 substituents        independently selected from the group consisting of        -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.2.a1) halogen;            -   1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(47a) wherein R^(47e) represents H or (C₁-C₃)alkyl,                or R⁴⁶ and R⁴⁷ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or                (C₁-C₃)alkyl; and            -   1.2.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   1.2.b) -(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.2.b1) halogen; and            -   1.2.b2) OR⁴⁹ wherein R⁴⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;        -   1.2.c) OR⁵⁰ wherein            -   R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or                —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.2.c1) halogen;            -   1.2.c2) OR⁵¹ wherein R⁵¹ represents H or (C₁-C₃)alkyl                which may optionally bear —(C₁-C₃)mono- or                di-alkylamino; and            -   1.2.c3) —NR⁵²R⁵³ in which R⁵² and R⁵³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵² and R⁵³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁵⁴ wherein R⁵⁴ represents H or (C₁-C₃)alkyl;        -   1.2.d) —C(O)—OR⁵⁵ wherein R⁵⁵ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;        -   1.2.e) —C(O)—NR⁵⁶R⁵⁷wherein            -   R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.e1) halogen;            -   1.2.e2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.2.e3) phenyl;            -   1.2.e4) —SO₂CH₃;            -   1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.2.e6) —NR⁵⁹R⁶⁰ in which R⁵⁹ and R⁶⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵⁹ and R⁶⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶¹ wherein R⁶¹ represents H or (C₁-C₃)alkyl;        -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -   R⁶² represents H or (C₁-C₃)alkyl; and            -   R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.2.f1) optionally substituted phenyl,            -   1.2.f2) OR⁶⁴ wherein R⁶⁴ represents H or (C₁-C₃)alkyl,                or            -   1.2.f3) NR⁶⁵R⁶⁶ wherein R⁶⁵ and R⁶⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁶⁵ and R⁶⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶⁷ wherein R⁶⁷ represents H or (C₁-C₃)alkyl;        -   1.2.g) —SO₂N⁶⁸R⁶⁹ wherein            -   R⁶⁵ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.g1) halogen;            -   1.2.g2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   1.2.g3) phenyl;            -   1.2.g4) —SO₂CH₃;            -   1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.2.g6 —NR⁷¹R⁷² in which R⁷¹ and R⁷² are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷¹ and R⁷² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷³ wherein R⁷³ represents H or (C₁-C₃)alkyl;        -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -   R⁷⁴ represents H or (C₁-C₃)alkyl, and            -   R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.2.h1) halogen;            -   1.2.h2) optionally substituted phenyl,            -   1.2.h3) OR⁷⁶ wherein R⁷⁶ represents H or (C₁-C₃)alkyl,                or            -   1.2.h4) NR⁷⁷R⁷⁸ wherein R⁷⁷ and R⁷⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷⁷ and R⁷⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷⁹ wherein R⁷⁹ represents H or (C₁-C₃)alkyl;        -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a)            wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹            may be joined and taken together with the N atom to which            they are attached form a 5-6 membered ring which may            optionally contain a ring member selected from O, S, and            NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl;        -   1.2.j) halogen;        -   1.2.k) optionally substituted phenyl;        -   1.2.l) NO₂;        -   1.2.m) CN; and        -   1.2.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;        -   1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   R² represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally    bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally    bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R⁴ represents    -   -   4.1) —(C₁-C₅)alkyl which is optionally substituted with        -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen            or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl;        -   4.1.b) -halogen;        -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl            which may optionally bear up to 3 substituents independently            selected from            -   4.1.c1) halogen;            -   4.1.c2) phenyl;            -   4.1.c3) —S(O)₂CH₃;            -   4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;        -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -   R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -   R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.1.d1) halogen;            -   4.1.d2) —S(O)₂CH₃;            -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹²⁰ wherein R¹²⁰                represents H or (C₁-C₃)alkyl;        -   4.1.e) optionally substituted phenyl; or        -   4.1.f) a 5-6 membered aromatic heterocycle containing up to            two heteroatoms selected from O, S, and N;

    -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   d represents 1, 2, or 3;        -   e represents 0 or 1;        -   f represents 0, 1, or 2;

    -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   g represents 1, 2, or 3;        -   h represents 0, 1, or 2;

    -   4.4)

wherein

-   -   -   R¹²⁵ represents        -   4.4.a) H;        -   4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in            turn is optionally substituted with halogen;        -   4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally            substituted phenyl, or —(C₁-C₃)alkyl which may optionally            bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or            (C₁-C₃)alkyl;        -   4.4.d) —C(O)R¹²⁹ wherein            -   R¹²⁹ represents            -   4.4.d1) optionally substituted phenyl,            -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.4.d2.1) halogen;                -   4.4.d2.2) optionally substituted phenyl;                -   4.4.d2.3) —S(O)₂—(C₁-C₄)alkyl which may optionally                    bear halogen;                -   4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₄)alkyl which may optionally bear halogen; and                -   4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;            -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹³⁷ wherein R¹³⁷                represents H or (C₁-C₃)alkyl; and        -   j represents 1, 2, or 3;

    -   4.5)

wherein

-   -   -   X represents C or N;        -   R¹³⁸ represents        -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   4.5.a1) halogen;            -   4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -   4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   4.5.b1) halogen; and            -   4.5.b2) OR¹⁴³ wherein R¹⁴³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   4.5.c) OR¹⁴⁴ wherein            -   R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.5.c1) halogen;            -   4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -   4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;        -   4.5.d) —C(O)—OR¹⁴⁹ wherein R¹⁴⁹ represents H or            —(C₁-C₄)alkyl which may optionally bear up to 3 halogens;        -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -   R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.e1) halogen;            -   4.5.e2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   4.5.e3) phenyl;            -   4.5.e4) —SO₂CH₃;            -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵                represents H or (C₁-C₃)alkyl;        -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -   R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -   R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.f1) optionally substituted phenyl,            -   4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl,                or            -   4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;        -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -   R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.g1) halogen;            -   4.5.g2) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;            -   4.5.g3) phenyl;            -   4.5.g4) —SO₂CH₃;            -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.g6) —NR¹⁶⁵R¹⁶⁵ in which R¹⁶⁵ and R¹⁶⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷                represents H or (C₁-C₃)alkyl;        -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -   R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -   R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.h1) halogen,            -   4.5.h2) optionally substituted phenyl,            -   4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -   4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;        -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H            or —(C₁-C₃)alkyl which may optionally bear halogen or            OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or            R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N            atom to which they are attached form a 5-6 membered ring            which may optionally contain a ring member selected from O,            S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;        -   4.5.j) halogen;        -   4.5.k) optionally substituted phenyl;        -   4.5.l) NO₂;        -   4.5.m) CN; or        -   4.5.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N; and

    -   k represents 0, 1, or 2;

    -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

m represents 1, 2, or 3;

-   -   4.7)

wherein

-   -   -   n represents 1, 2, or 3; and        -   p represents 0, 1, or 2;

    -   4.8)

wherein

-   -   -   q represents 1, 2, or 3;

    -   4.9)

wherein

-   -   -   R¹⁷⁸ represents        -   4.9.a) H;        -   4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally            substituted with halogen;        -   4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen;        -   4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen;        -   4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally            substituted phenyl or —(C₁-C₃)alkyl, which may be            substituted with halogen or —R¹⁸¹ wherein R¹⁸¹ represents H            or (C₁-C₃)alkyl which may optionally bear halogen;

    -   4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted        phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3        substituents independently selected from        -   -   4.9.f1) halogen;            -   4.9.f2) optionally substituted phenyl;            -   4.9.f3) —S(O)₂CH₃;            -   4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(185a) wherein R^(185a) represents H                or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁸⁶                wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl;

        -   4.9g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or

        -   4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each            independently represents H or —(C₁-C₄)alkyl which may            optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents            H or (C₁-C₃)alkyl;

        -   r represents 0, 1, or 2; and

        -   s represents 0 or 1;

    -   4.10)

wherein

-   -   -   R¹⁹¹ represents        -   4.10.a) H;        -   4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;        -   4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or            —(C₁-C₃)alkyl, both of which may be substituted with halogen            or —(C₁-C₃)alkyl;        -   4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which            may optionally bear up to 3 substituents independently            selected from            -   4.10.d1) halogen;            -   4.10.d2) phenyl;            -   4.10.d3)—S(O)₂CH₃;            -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(197a) wherein R^(197a) represents H                or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁸                wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl;        -   4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or        -   4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR²⁰² wherein R²⁰² represents            H or (C₁-C₃)alkyl; and        -   X represents O, S, S(O), S(O)₂, or NR²⁰³ wherein R²⁰³            represents H or (C₁-C₃)alkyl; and        -   t represents 0, 1, or 2;

    -   4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted        phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3        substituents independently selected from        -   4.11.a) halogen;        -   4.11.b) optionally substituted phenyl;        -   4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and        -   4.11.d)

-   -   4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently        represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and        taken together with the N atom to which they are attached form a        5-6 membered ring which may optionally contain a ring member        selected from O and S, said alkyl or ring optionally bearing up        to 3 substituents independently selected from        -   4.12.a) halogen;        -   4.12.b) optionally substituted phenyl;        -   4.12.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and        -   4.12.d)

-   -   4.13) halogen; or    -   4.14) CN;    -   or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention provides a compound offormula (I)

-   wherein:-   X⁰ represents C or N;-   R¹ represents    -   1.1) phenyl which may optionally bear up to 4 substituents        independently selected from the group consisting of        -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.1.a1) halogen;            -   1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or                —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(7a) wherein R^(7a) represents H or (C₁-C₃)alkyl, or                R⁶ and R⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -   1.1.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.1.b1) halogen;        -   1.1.c) OR¹⁰ wherein            -   R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.1.c1) halogen;            -   1.1c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -   1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;        -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -   R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.1.e1) halogen;            -   1.1.e3) phenyl;            -   1.1.e4) —SO₂CH₃;            -   1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;        -   1.1.f) —N(R)—C(O)—R²³ wherein            -   R²² represents H or (C₁-C₃)alkyl; and            -   R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.1.f1) optionally substituted phenyl,            -   1.1.f2) OR²⁴ wherein R²⁴ represents H or (C₁-C₃)alkyl,                or            -   1.1.f3) NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R²⁵ and R²⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²⁷ wherein R²⁷ represents H or (C₁-C₃)alkyl;        -   1-1.g) —SO₂NR²⁸R²⁹ wherein            -   R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -   1.1.g1) halogen;            -   1.1.g3) phenyl;            -   1.1.g4) —SO₂CH₃;            -   1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;        -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -   R³⁴ represents H or (C₁-C₃)alkyl, and            -   R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.1.h1) halogen;            -   1.1.h2) optionally substituted phenyl,            -   1.1.h3) OR³⁶ wherein R³⁶ represents H or (C₁-C₃)alkyl,                or            -   1.1.h4) NR³⁷R³⁸ wherein R³⁷ and R³⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³⁷ and R³⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³⁹ wherein R³⁹ represents H or (C₁-C₃)alkyl;        -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in            which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may            be joined and taken together with the N atom to which they            are attached form a 5-6 membered ring which may optionally            contain a ring member selected from O, S, and NR⁴³ wherein            R⁴³ represents H or (C₁-C₃)alkyl;        -   1.1j) halogen;        -   1.1.l) NO₂;        -   1.1.m) CN; and        -   1.1.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;        -   1.1.o) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   or-   R¹ represents    -   1.2) a 5-6 membered aromatic heterocycle containing up to 3        heteroatoms independently selected from the group consisting of        N, O, and S; said R¹ heterocycle optionally bearing up to 4        substituents independently selected from the group consisting of        -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.2.a1) halogen;            -   1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen or                OR^(47a) wherein R^(47a) represents H or (C₁-C₃)alkyl,                or R⁴⁶ and R⁴⁷ may be joined and taken together with the                N atom to which they are attached form a 5-6 membered                ring which may optionally contain a ring member selected                from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or                (C₁-C₃)alkyl; and            -   1.2.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.2.b1) halogen;        -   1.2.c) OR⁵⁰ wherein            -   R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or                —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.2.c1) halogen;            -   1.2.c2) OR⁵¹ wherein R⁵¹ represents H or (C₁-C₃)alkyl                which may optionally bear —(C₁-C₃)mono- or                di-alkylamino; and            -   1.2.c3) —NR⁵²R⁵³ in which R⁵² and R⁵³ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵² and R⁵³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁵⁴ wherein R⁵⁴ represents H or (C₁-C₃)alkyl;        -   1.2.e) —C(O)—NR⁵⁶R⁵⁷wherein            -   R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.e1) halogen;            -   1.2.e3) phenyl;            -   1.2.e4) —SO₂CH₃;            -   1.2.e5) —OR⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.2.e6) —NR⁵⁹R⁶⁰ in which R⁵⁹ and R⁶⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁵⁹ and R⁶⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶¹ wherein R⁶¹ represents H or (C₁-C₃)alkyl;        -   1.2.f) —N(R⁶)—C(O)—R⁶³ wherein            -   R⁶² represents H or (C₁-C₃)alkyl; and            -   R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.2.f1) optionally substituted phenyl,            -   1.2.f2) OR⁶⁴ wherein R⁶⁴ represents H or (C₁-C₃)alkyl,                or            -   1.2.f3) NR⁶⁵R⁶⁶ wherein R⁶⁵ and R⁶⁶ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁶⁵ and R⁶⁶ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁶⁷ wherein R⁶⁷ represents H or (C₁-C₃)alkyl;        -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -   R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.g1) halogen;            -   1.2.g3) phenyl;            -   1.2.g4) —SO₂CH₃;            -   1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.2.g6 —NR⁷¹R⁷² in which R⁷¹ and R⁷² are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷¹ and R⁷² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷³ wherein R⁷³ represents H or (C₁-C₃)alkyl;        -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -   R⁷⁴ represents H or (C₁-C₃)alkyl, and            -   R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.2.h1) halogen;            -   1.2.h2) optionally substituted phenyl,            -   1.2.h3) OR⁷⁶ wherein R⁷⁶ represents H or (C₁-C₃)alkyl,                or            -   1.2.h4) NR⁷⁷R⁷⁸ wherein R⁷⁷ and R⁷⁸ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁷⁷ and R⁷⁸ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁷⁹ wherein R⁷⁹ represents H or (C₁-C₃)alkyl;        -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently 1 or            —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a)            wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹            may be joined and taken together with the N atom to which            they are attached form a 5-6 membered ring which may            optionally contain a ring member selected from O, S, and            NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl;        -   1.2.j) halogen;        -   1.2.k) optionally substituted phenyl;        -   1.2.l) NO₂;        -   1.2.m) CN; and        -   1.2.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N;        -   1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear    halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally    bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R⁴ represents    -   4.1) —(C₁-C₅)alkyl which is optionally substituted with        -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen            or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl;        -   4.1.b) -halogen;        -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl            which may optionally bear up to 3 substituents independently            selected from            -   4.1.c1) halogen;            -   4.1.c2) phenyl;            -   4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;        -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein R¹¹⁵ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen and            -   R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.1.d1) halogen;            -   4.1.d2) —S(O)₂CH₃;            -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹²⁰ wherein R¹²⁰                represents H or (C₁-C₃)alkyl; or        -   4.1.f) a 5-6 membered aromatic heterocycle containing up to            two heteroatoms selected from O, S, and N;    -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   d represents 1, 2, or 3;        -   e represents 0 or 1;        -   f represents 0, 1, or 2;

    -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²³ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   g represents 1, 2, or 3;        -   h represents 0, 1, or 2;

    -   4-4)

wherein

-   -   -   R¹²⁵ represents        -   4.4.a) H;        -   4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in            turn is optionally substituted with halogen;        -   4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally            substituted phenyl, or —(C₁-C₃)alkyl which may optionally            bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or            (C₁-C₃)alkyl;        -   4.4.d) —C(O)R¹²⁹ wherein            -   R¹²⁹ represents            -   4.4.d1) optionally substituted phenyl,            -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.4.d2.1) halogen;                -   4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;            -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹³⁷ wherein R¹³⁷                represents H or (C₁-C₃)alkyl; and            -   j represents 1, 2, or 3;

    -   4.5)

wherein

-   -   -   X represents C or N;        -   R¹³⁸ represents        -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   4.5.a1) halogen;            -   4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   4.5.a3) —NR¹⁴¹R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -   4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   4.5.b1) halogen;        -   4.5.c) OR¹⁴⁴ wherein            -   R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.5.c1) halogen;            -   4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -   4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;        -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -   R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.e1) halogen;            -   4.5.e3) phenyl;            -   4.5.e4) —SO₂CH₃;            -   4.5.e5) —OR⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵                represents H or (C₁-C₃)alkyl;        -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein R¹⁵⁶ represents H or            (C₁-C₃)alkyl; and R¹⁵⁷ represents H, optionally substituted            phenyl, or (C₁-C₄)alkyl which is optionally substituted with            -   4.5.f2) optionally substituted phenyl,            -   4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl,                or            -   4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;        -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -   R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.g1) halogen;            -   4.5.g3) phenyl;            -   4.5.g4) —SO₂CH₃;            -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷                represents H or (C₁-C₃)alkyl;        -   4.5.h) —N(R¹⁶⁸)—SO₂—R⁶⁹ wherein            -   R¹⁶⁸ represents H or (C₁-C₃)alkyl, and            -   R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.h1) halogen,            -   4.5.h2) optionally substituted phenyl,            -   4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -   4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;        -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H            or —(C₁-C₃)alkyl which may optionally bear halogen or            OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or            R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N            atom to which they are attached form a 5-6 membered ring            which may optionally contain a ring member selected from O,            S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;        -   4.5j) halogen;        -   4.5.1) NO₂;        -   4.5.m) CN; or        -   4.5.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N; and        -   k represents 0, 1, or 2;

    -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   -   m represents 1, 2, or 3;

        -   4.7)

wherein

-   -   -   -   n represents 1, 2, or 3; and            -   p represents 0, 1, or 2;

        -   4.8)

wherein

-   -   -   -   q represents 1, 2, or 3;

        -   4.9)

wherein

-   -   -   -   R¹⁷⁸ represents

        -   4.9.a) H;

        -   4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally            substituted with halogen;

        -   4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen;

        -   4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen;

        -   4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally            substituted phenyl or —(C₁-C₃)alkyl, which may be            substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H            or (C₁-C₃)alkyl which may optionally bear halogen;

        -   4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally            substituted phenyl or —(C₁-C₃)alkyl which may optionally            bear up to 3 substituents independently selected from            -   4.9.f1) halogen;            -   4.9.f2) optionally substituted phenyl;            -   4.9.f3) —S(O)₂CH₃;            -   4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(185a) wherein R^(185a) represents H                or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁸⁶                wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl;

        -   4.9g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or

        -   4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each            independently represents H or —(C₁-C₄)alkyl which may            optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents            H or (C₁-C₃)alkyl;

        -   r represents 0, 1, or 2; and

        -   S represents 0 or 1;

    -   4.10)

wherein

-   -   -   R¹⁹¹ represents        -   4.10.a) H;        -   4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —R¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;        -   4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or            —(C₁-C₃)alkyl, both of which may be substituted with halogen            or —(C₁-C₃)alkyl;        -   4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which            may optionally bear up to 3 substituents independently            selected from            -   4.10.d1) halogen;            -   4.10.d2) phenyl;            -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(197a) wherein R^(197a) represents H                or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁸                wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl;        -   4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or        -   4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR²⁰² wherein R²⁰² represents            H or (C₁-C₃)alkyl; and        -   X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H            or —(C₁-C₃)alkyl; and        -   t represents 0, 1, or 2;

    -   4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted        phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3        substituents independently selected from        -   4.11.a) halogen;        -   4.11.b) optionally substituted phenyl;        -   4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or C₁-C₃)alkyl which            may optionally bear halogen; and        -   4.11.d)

-   -   4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently        represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and        taken together with the N atom to which they are attached form a        5-6 membered ring which may optionally contain a ring member        selected from O and S, said alkyl or ring optionally bearing up        to 3 substituents independently selected from        -   4.12.a) halogen;        -   4.12.b) optionally substituted phenyl;        -   4.12.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and        -   4.12.d)

-   -   4.13) halogen; or    -   4.14) CN;

-   or a pharmaceutically acceptable salt thereof.

In yet another preferred embodiment, the present invention provides acompound of formula (I)

-   wherein:-   X¹ represents C;-   R¹ represents    -   1.1) phenyl which may optionally bear up to 4 substituents        independently selected from the group consisting of        -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.1.a1) halogen;            -   1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or                —(C₁-C₃)alkyl which may optionally bear halogen or R⁶                and R⁷ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -   1.1.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;        -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.1.b1) halogen;        -   1.1.c) OR¹⁰ wherein            -   R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.1.c1) halogen;            -   1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl;                and            -   1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;        -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -   R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.1.e1) halogen;            -   1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;        -   1.1.f) —N(R²)—C(O)—R²³ wherein            -   R²² represents H or (C₁-C₃)alkyl; and            -   R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;        -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -   R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R²⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with:            -   1.1.g1) halogen;            -   1.1.g4) —SO₂CH₃;            -   1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;        -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -   R³⁴ represents H or (C₁-C₃)alkyl, and            -   R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.1.h1) halogen;        -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in            which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may            be joined and taken together with the N atom to which they            are attached form a 5-6 membered ring which may optionally            contain a ring member selected from O, S, and NR⁴³ wherein            R⁴³ represents H or (C₁-C₃)alkyl;        -   1.1 j) halogen;        -   1.1.l) NO₂;        -   1.1.m) CN; and        -   1.1.n) an imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, or furan;        -   1.1.o) —C(O)—R²⁰¹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   or-   R¹ represents    -   1.2) a 5-6 membered aromatic heterocycle selected from        imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine,        isoxazole, isothiazole, thiophene, and furan; said R¹        heterocycle optionally bearing up to 4 substituents        independently selected from the group consisting of        -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.2.a1) halogen;            -   1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁴⁶ and R⁴⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl;                and            -   1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;        -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.2.b1) halogen;        -   1.2.c) OR⁵⁰ wherein            -   R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or                —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.2.c1) halogen;        -   1.2.e) —C(O)—NR⁵⁶R⁵⁷wherein            -   R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.e1) halogen; or        -   1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl which            may optionally bear halogen;        -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -   R⁶² represents H or (C₁-C₃)alkyl; and            -   R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;        -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -   R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.g1) halogen; or            -   1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -   R⁷⁴ represents H or (C₁-C₃)alkyl, and            -   R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.2.h1) halogen;        -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a)            wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹            may be joined and taken together with the N atom to which            they are attached form a 5-6 membered ring which may            optionally contain a ring member selected from O, S, and            NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl;        -   1.2.j) halogen;        -   1.2.k) optionally substituted phenyl;        -   1.2.l) NO₂;        -   1.2.m) CN; and        -   1.2.n) an imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, or furan;        -   1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear    halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally    bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R⁴ represents    -   4.1) —(C₁-C₅)alkyl which is optionally substituted with        -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen            or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl;        -   4.1.b) -halogen;        -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl            which may optionally bear up to 3 substituents independently            selected from            -   4.1.c1) halogen;            -   4.1.c2) phenyl;            -   4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;        -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -   R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -   R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.1.d1) halogen;            -   4.1.d2) —S(O)₂CH₃;            -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹²⁰ wherein R¹²⁰                represents H or (C₁-C₃)alkyl; or        -   4.1.f) a 5-6 membered aromatic heterocycle containing up to            two heteroatoms selected from O, S, and N;    -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   d represents 1, 2, or 3;        -   e represents 0 or 1;        -   f represents 0, 1, or 2;

    -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   g represents 1, 2, or 3;        -   h represents 0, 1, or 2;

    -   4.4)

wherein

-   -   -   R¹²⁵ represents        -   4.4.a) H;        -   4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in            turn is optionally substituted with halogen;        -   4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally            substituted phenyl, or —(C₁-C₃)alkyl which may optionally            bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or            (C₁-C₃)alkyl;        -   4.4.d) —C(O)R¹²⁹ wherein            -   R¹²⁹ represents            -   4.4.d1) optionally substituted phenyl,            -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.4.d2.1) halogen;                -   4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;

4.4.d3) —R¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl which may optionallybear halogen; or

-   -   -   -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹³⁷ wherein R¹³⁷                represents H or (C₁-C₃)alkyl; and

        -   j represents 1, 2, or 3;

    -   4.5)

wherein

-   -   -   X represents C or N;        -   R¹³⁸ represents        -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   4.5.a1) halogen;            -   4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -   4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   4.5.b1) halogen;        -   4.5.c) OR¹⁴⁴ wherein            -   R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.5.c1) halogen;            -   4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -   4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;            -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein R¹⁵⁰ represents H or                (C₁-C₃)alkyl which may optionally bear halogen; and            -   R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.e1) halogen;            -   4.5.e3) phenyl;            -   4.5.e4) —SO₂CH₃;            -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵                represents H or (C₁-C₃)alkyl;        -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -   R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -   R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.f1) optionally substituted phenyl,            -   4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl,                or            -   4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;        -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -   R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.g1) halogen;            -   4.5.g3) phenyl;            -   4.5.g4) —SO₂CH₃;            -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷                represents H or (C₁-C₃)alkyl;        -   4.5.h) —N(R¹⁶⁸)—SOR¹⁶⁹ wherein            -   R¹⁶⁸represents H or (C₁-C₃)alkyl, and            -   R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.h1) halogen,            -   4.5.h2) optionally substituted phenyl,            -   4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -   4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;        -   4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H            or —(C₁-C₃)alkyl which may optionally bear halogen or OR¹⁷⁵,            wherein R^(175a) represents H or (C₁-C₃)alkyl, or R¹⁷⁴ and            R¹⁷⁵ may be joined and taken together with the N atom to            which they are attached form a 5-6 membered ring which may            optionally contain a ring member selected from O, S, and            NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;        -   4.5.j) halogen;        -   4.5.l) NO₂;        -   4.5.m) CN; or        -   4.5.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N; and

    -   k represents 0, 1, or 2;

    -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   m represents 1, 2, or 3;

    -   4.7)

wherein

-   -   -   n represents 1, 2, or 3; and        -   p represents 0, 1, or 2;

    -   4.8)

wherein

-   -   -   q represents 1, 2, or 3;

    -   4.9)

wherein

-   -   -   R¹⁷⁸ represents        -   4.9.a) H;        -   4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally            substituted with halogen;        -   4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen;        -   4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen;        -   4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally            substituted phenyl or —(C₁-C₃)alkyl, which may be            substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H            or (C₁-C₃)alkyl which may optionally bear halogen;        -   4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally            substituted phenyl or —(C₁-C₃)alkyl which may optionally            bear up to 3 substituents independently selected from            -   4.9.f1) halogen;            -   4.9.f2) optionally substituted phenyl;            -   4.9.f3) —S(O)₂CH₃;            -   4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(185a) wherein R^(185a) represents H                or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁸⁶                wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl;        -   4.9g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or        -   4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each            independently represents H or —(C₁-C₄)alkyl which may            optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents            H or (C₁-C₃)alkyl;        -   r represents 0, 1, or 2; and        -   s represents 0 or 1;

    -   4.10)

wherein

-   -   -   R¹⁹¹ represents        -   4.10.a) H;        -   4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;        -   4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or            —(C₁-C₃)alkyl, both of which may be substituted with halogen            or —(C₁-C₃)alkyl;        -   4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which            may optionally bear up to 3 substituents independently            selected from            -   4.10.d1) halogen;            -   4.10.d2) phenyl;            -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(197a) wherein R^(197a) represents H                or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁸                wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl;        -   4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or        -   4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR²⁰² wherein R²⁰² represents            H or (C₁-C₃)alkyl; and        -   X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H            or —(C₁-C₃)alkyl; and        -   t represents 0, 1, or 2;

    -   4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted        phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3        substituents independently selected from        -   4.11.a) halogen;        -   4.11.b) optionally substituted phenyl;        -   4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and        -   4.11.d)

-   -   4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently        represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and        taken together with the N atom to which they are attached form a        5-6 membered ring which may optionally contain a ring member        selected from O and S, said alkyl or ring optionally bearing up        to 3 substituents independently selected from        -   4.12.a) halogen;        -   4.12.b) optionally substituted phenyl;        -   4.12.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and    -   4.12.d)

-   -   4.13) halogen; or    -   4.14) CN;

-   or a pharmaceutically acceptable salt thereof.

In still yet another preferred embodiment, the present inventionprovides a compound of formula (I)

-   wherein:-   X⁰ represents C;-   R¹ represents    -   1.1) phenyl which may optionally bear up to 4 substituents        independently selected from the group consisting of        -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.1.a1) halogen;            -   1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or                —(C₁-C₃)alkyl which may optionally bear halogen or R⁶                and R⁷ may be joined and taken together with the N atom                to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl;                and            -   1.1.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;        -   1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.1.b1) halogen;        -   1.1.c) OR¹⁰ wherein            -   R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.1.c1) halogen;            -   1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl;                and            -   1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H                or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹² and R¹³ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl;        -   1.1.e) —C(O)—NR¹⁶R¹⁷ wherein            -   R¹⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.1.e1) halogen;            -   1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R¹⁹ and R²⁰ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl;        -   1.1.f) —N(R²²)—C(O)—R²³ wherein            -   R²² represents H or (C₁-C₃)alkyl; and            -   R²³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;        -   1.1.g) —SO₂NR²⁸R²⁹ wherein            -   R²⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R²⁹ represents H or -(C₁-C₄)alkyl which is optionally                substituted with:            -   1.1.g1) halogen;            -   1.1.g4) —SO₂CH₃;            -   1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R³¹ and R³² may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl;        -   1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein            -   R³⁴ represents H or (C₁-C₃)alkyl, and            -   R³⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.1.h1) halogen;        -   1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in            which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may            be joined and taken together with the N atom to which they            are attached form a 5-6 membered ring which may optionally            contain a ring member selected from O, S, and NR⁴³ wherein            R⁴³ represents H or (C₁-C₃)alkyl;        -   1.1.j) halogen;        -   1.1.l) NO₂;        -   1.1.m) CN ;and        -   1.1.n) an imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, or furan;        -   1.1.o) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   or-   R¹ represents    -   1.2) a 5-6 membered aromatic heterocycle selected from        imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine,        isoxazole, isothiazole, thiophene, and furan; said R¹        heterocycle optionally bearing up to 4 substituents        independently selected from the group consisting of        -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   1.2.a1) halogen;            -   1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;            -   1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently                H or —(C₁-C₃)alkyl which may optionally bear halogen, or                R⁴⁶ and R⁴⁷ may be joined and taken together with the N                atom to which they are attached form a 5-6 membered ring                which may optionally contain a ring member selected from                O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl;                and            -   1.2.a4) an imidazole, thiazole, oxazole, pyridine,                pyrazole, pyrimidine, isoxazole, isothiazole, thiophene,                or furan;        -   1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   1.2.b1) halogen;        -   1.2.c) OR⁵⁰wherein            -   R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or                —(C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   1.2.c1) halogen;        -   1.2.e) —C(O)—NR⁵⁶R⁵⁷wherein            -   R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.e1) halogen; or            -   1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein            -   R⁶² represents H or (C₁-C₃)alkyl; and            -   R⁶³ represents optionally substituted phenyl, or                (C₁-C₄)alkyl;        -   1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein            -   R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   1.2.g1) halogen; or            -   1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein            -   R⁷⁴ represents H or (C₁-C₃)alkyl, and            -   R⁷⁵ represents optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   1.2.h1) halogen;        -   1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or            —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a)            wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹            may be joined and taken together with the N atom to which            they are attached form a 5-6 membered ring which may            optionally contain a ring member selected from O. S, and            NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl;        -   1.2.j) halogen;        -   1.2.k) optionally substituted phenyl;        -   1.2.l) NO₂;        -   1.2.m) CN; and        -   1.2.n) an imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, or furan;        -   1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear    halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally    bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R⁴ represents    -   4.1) —(C₁-C₅)alkyl which is optionally substituted with        -   4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen            or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl;        -   4.1.b) -halogen;        -   4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl            which may optionally bear up to 3 substituents independently            selected from            -   4.1.c1) halogen;            -   4.1.c2) phenyl;            -   4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹² and R¹¹³ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴                represents H or (C₁-C₃)alkyl;        -   4.1.d) —NR¹¹⁵R¹¹⁶ wherein            -   R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -   R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.1.d1) halogen;            -   4.1.d2) —S(O)₂CH₃;            -   4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹²⁰ wherein R¹²⁰                represents H or (C₁-C₃)alkyl; or        -   4.1.f) a 5-6 membered aromatic heterocycle containing up to            two heteroatoms selected from O, S, and N;    -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl;

-   -   -   d represents 1, 2, or 3;        -   e represents 0 or 1;        -   f represents 0, 1, or 2;

    -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogenor —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl;

-   -   -   g represents 1, 2, or 3;        -   h represents 0, 1, or 2;

    -   4.4)

wherein

-   -   -   R¹²⁵ represents        -   4.4.a) H;        -   4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in            turn is optionally substituted with halogen;        -   4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally            substituted phenyl, or —(C₁-C₃)alkyl which may optionally            bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or            (C₁-C₃)alkyl;        -   4.4.d) —C(O)R¹²⁹ wherein            -   R¹²⁹ represents            -   4.4.d1) optionally substituted phenyl,            -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.4.d2.1) halogen;                -   4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen; and                -   4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are                    independently H or —(C₁-C₃)alkyl which may                    optionally bear halogen, or R¹³¹ and R¹³² may be                    joined and taken together with the N atom to which                    they are attached form a 5-6 membered ring which may                    optionally contain a ring member selected from O, S,                    and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl;            -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹³⁷ wherein R¹³⁷                represents H or (C₁-C₃)alkyl; and            -   j represents 1, 2, or 3;

    -   4.5)

wherein

-   -   -   X represents C or N;        -   R¹³⁸ represents        -   4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3            substituents independently selected from            -   4.5.a1) halogen;            -   4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl                which may optionally bear halogen or —(C₁-C₃)mono- or                di-alkylamino;            -   4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(141a) wherein R^(141a) represents H                or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁴²                wherein R¹⁴² represents H or (C₁-C₃)alkyl; and            -   4.5.a4) a 5-6 membered heteroaromatic containing up to                two heteroatoms selected from O, S, and N;        -   4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2            substituents independently selected from            -   4.5.b1) halogen;        -   4.5.c) OR¹⁴⁴ wherein            -   R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or                (C₁-C₄)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.5.c1) halogen;            -   4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl                which may optionally bear (C₁-C₃)mono- or di-alkylamino;                and            -   4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸                represents H or (C₁-C₃)alkyl;        -   4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein            -   R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.e1) halogen;            -   4.5.e3) phenyl;            -   4.5.e4) —SO₂CH₃;            -   4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵                represents H or (C₁-C₃)alkyl;        -   4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein            -   R¹⁵⁶ represents H or (C₁-C₃)alkyl; and            -   R¹⁵⁷ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.f1) optionally substituted phenyl,            -   4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl,                or            -   4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹                represents H or (C₁-C₃)alkyl;        -   4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein            -   R¹⁶² represents H or (C₁-C₃)alkyl which may optionally                bear halogen; and            -   R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally                substituted with            -   4.5.g1) halogen;            -   4.5.g3) phenyl;            -   4.5.g4) —SO₂CH₃;            -   4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; or            -   4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷                represents H or (C₁-C₃)alkyl;        -   4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein            -   R¹⁶⁸represents H or (C₁-C₃)alkyl, and            -   R¹⁶⁹ represents H, optionally substituted phenyl, or                (C₁-C₄)alkyl which is optionally substituted with            -   4.5.h1) halogen,            -   4.5.h2) optionally substituted phenyl,            -   4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl                which may optionally bear halogen, or            -   4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken                together with the N atom to which they are attached form                a 5-6 membered ring which may optionally contain a ring                member selected from O, S, and NR¹⁷³ wherein R¹⁷³                represents H or (C₁-C₃)alkyl;        -   4.5.i) NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H            or —(C₁-C₃)alkyl which may optionally bear halogen or            OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or            R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N            atom to which they are attached form a 5-6 membered ring            which may optionally contain a ring member selected from O,            S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl;        -   4.5.j) halogen;        -   4.5.1) NO₂        -   4.5.m) CN; or        -   4.5.n) a 5-6 membered heteroaromatic containing up to two            heteroatoms selected from O, S, and N; and

    -   k represents 0, 1, or 2;

    -   4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   m represents 1, 2, or 3;

    -   4.7)

wherein

-   -   -   n represents 1, 2, or 3; and        -   p represents 0, 1, or 2;

    -   4.8)

wherein

-   -   -   q represents 1, 2, or 3;

    -   4.9)

wherein

-   -   -   R¹⁷⁸ represents        -   4.9.a) H;        -   4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or            —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally            substituted with halogen;        -   4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen;        -   4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen;        -   4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally            substituted phenyl or —(C₁-C₃)alkyl, which may be            substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H            or (C₁-C₃)alkyl which may optionally bear halogen;        -   4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally            substituted phenyl or —(C₁-C₃)alkyl which may optionally            bear up to 3 substituents independently selected from            -   4.9.f1) halogen;            -   4.9.f2) optionally substituted phenyl;            -   4.9.f3) —S(O)₂CH₃;            -   4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(185a) wherein R^(185a) represents H                or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁸⁶                wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl;        -   4.9g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or        -   4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each            independently represents H or —(C₁-C₄)alkyl which may            optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents            H or (C₁-C₃)alkyl;        -   r represents 0, 1, or 2; and        -   s represents 0 or 1;

    -   4.10)

wherein

-   -   -   R¹⁹¹ represents        -   4.10.a) H;        -   4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or            OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl;        -   4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or            —(C₁-C₃)alkyl, both of which may be substituted with halogen            or —(C₁-C₃)alkyl;        -   4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which            may optionally bear up to 3 substituents independently            selected from            -   4.10.d1) halogen;            -   4.10.d2) phenyl;            -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen; and            -   4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen or OR^(197a) wherein R^(197a) represents H                or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and                taken together with the N atom to which they are                attached form a 5-6 membered ring which may optionally                contain a ring member selected from O, S, and NR¹⁹⁸                wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl;        -   4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or        -   4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and            taken together with the N atom to which they are attached            form a 5-6 membered ring which may optionally contain a ring            member selected from O, S, and NR²⁰² wherein R²⁰² represents            H or (C₁-C₃)alkyl; and        -   X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H            or —(C₁-C₃)alkyl; and        -   t represents 0, 1, or 2;

    -   4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted        phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3        substituents independently selected from        -   4.11.a) halogen;        -   4.11.b) optionally substituted phenyl;        -   4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and        -   4.11.d)

-   -   4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently        represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and        taken together with the N atom to which they are attached form a        5-6 membered ring which may optionally contain a ring member        selected from O and S, said alkyl or ring optionally bearing up        to 3 substituents independently selected from        -   4.12.a) halogen;        -   4.12.b) optionally substituted phenyl;        -   4.12.c) OR²⁰⁵ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and        -   4.12.d)

-   -   4.13) halogen; or    -   4.14) CN;

-   or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound offormula (I)

-   wherein:-   X⁰ represents C or N;-   R¹ represents    -   1.1) phenyl which may optionally bear up to 4 substituents        independently selected from the group consisting of        -   1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3            halogen substituents;        -   1.1.b) OR¹⁰ wherein R¹⁰ represents H; phenyl; benzyl;            (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear            up to 3 halogen substituents;        -   1.1.c) halogen; and        -   1.1.d) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   or-   R¹ represents    -   1.2) a 5-6 membered aromatic heterocycle selected from        imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine,        isoxazole, isothiazole, thiophene, and furan; said R¹        heterocycle optionally bearing up to 4 substituents        independently selected from the group consisting of        -   1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3            halogen substituents;        -   1.2.b) OR⁵⁰ wherein R⁵⁰ represents H; phenyl; benzyl;            —(C₃-C₆)cycloalkyl; or —(C₁-C₄)alkyl which may optionally            bear up to 3 halogen substituents;        -   1.2.c) halogen; and        -   1.2.d) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl            which may optionally bear up to 3 halogens;-   R² represents halogen; —(C₁-C₅)alkyl which may optionally bear    halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally    bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen;-   R⁴ represents    -   4.1) —(C₁-C₅)alkyl which is optionally substituted with        -   4.1.a) -halogen;        -   4.1.b) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl            which may optionally bear up to 3 halogen substituents        -   4.1.c) —NR¹¹⁵R¹¹⁶ wherein            -   R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally                bear halogen and            -   R¹¹⁶ represents H, optionally substituted phenyl, or                —(C₁-C₅)alkyl which may optionally bear up to 3                substituents independently selected from            -   4.1.c1) halogen; and            -   4.1.c2) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;    -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —O—(C₁-C₃)alkyl;

-   -   -   d represents 1, 2, or 3;        -   e represents 0 or 1;        -   f represents 0, 1, or 2;

    -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   g represents 1, 2, or 3;        -   h represents 0, 1, or 2;

    -   4.4)

wherein

-   -   -   R¹²⁵ represents        -   4.4.a) H;        -   4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen;        -   4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally            substituted phenyl, or —(C₁-C₃)alkyl which may optionally            bear halogen;        -   4.4.d) —C(O)R¹²⁹ wherein            -   R¹²⁹ represents            -   4.4.d1) optionally substituted phenyl,            -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.4.d2.1) halogen; and                -   4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;            -   4.4.d3) —R¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl; or            -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen; and        -   j represents 1, 2, or 3;

    -   4.5)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   m represents 1, 2, or 3;

    -   4.6)

wherein

-   -   -   n represents 1, 2, or 3; and        -   p represents 0, 1, or 2;

    -   4.7)

wherein

-   -   -   q represents 1, 2, or 3;

    -   4.8)

wherein

-   -   -   R¹⁷⁸ represents        -   4.8.a) H;        -   4.8.b) —(C₁-C₃)alkyl which may optionally bear halogen;        -   4.8.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally            substitutued phenyl or —(C₁-C₃)alkyl, which may be            substituted with halogen;        -   4.8.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally            substituted phenyl or —(C₁-C₃)alkyl which may optionally            bear up to 3 substituents independently selected from            -   4.9.d1) halogen; and            -   4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   4.8e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl; or        -   4.8.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen;        -   r represents 0, 1, or 2; and        -   s represents 0 or 1;

    -   4.9)

wherein

-   -   -   R¹⁹¹ represents        -   4.9.a) H;        -   4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen;        -   4.9.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or            —(C₁-C₃)alkyl, both of which may be substituted with            halogen;        -   4.9.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which            may optionally bear up to 3 substituents independently            selected from            -   4.10.d1) halogen;            -   4.10.d2) phenyl; and            -   4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   4.9.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or        -   4.9.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen;        -   X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H            or —(C₁-C₃)alkyl; and        -   t represents 0, 1, or 2;

    -   4.10) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted        phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3        substituents independently selected from        -   4.10.a) halogen;        -   4.10.b) optionally substituted phenyl;        -   4.10.c) OR²⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and

    -   4.10.d)

-   -   4.11) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently        represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and        taken together with the N atom to which they are attached form a        5-6 membered ring which may optionally contain a ring member        selected from O and S, said alkyl or ring optionally bearing up        to 3 substituents independently selected from        -   4.11.a) halogen;        -   4.11.b) optionally substituted phenyl;        -   4.11.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl            which may optionally bear halogen; and    -   4.11.d)

-   -   4.12) halogen; or    -   4.13) CN;

-   or a pharmaceutically acceptable salt thereof.

In still another preferred embodiment, the present invention provides acompound of formula (I)

-   wherein:-   X⁰ represents C;-   R¹ represents    -   1.1) phenyl bearing 1 or 2 substituents independently selected        from the group consisting of        -   1.1.a) methyl;        -   1.1.b) trifluoromethyl; and        -   1.1.c) halogen;        -   1.1.d) —C(O)—(C₁-C₄)alkyl which may optionally bear up to 3            halogens;-   or-   R¹ represents    -   -   1.2) a 5-6 membered aromatic heterocycle selected from            imidazole, thiazole, oxazole, pyridine, pyrazole,            pyrimidine, isoxazole, isothiazole, thiophene, and furan;            said R¹ heterocycle optionally bearing up to 4 substituents            independently selected from the group consisting of        -   1.2.a) methyl;        -   1.2.b) trifluoromethyl;        -   1.2.c) halogen; and        -   1.2.d) —C(O)—(C₁-C₄)alkyl which may optionally bear up to 3            halogens;-   R² represents halogen;-   R³ represents hydrogen or halogen; and-   R⁴ represents    -   4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogenor —O—(C₁-C₃)alkyl;

-   -   -   d represents 1, 2, or 3;        -   e represents 0 or 1;        -   f represents 0, 1, or 2;

    -   4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen;

-   -   -   g represents 1, 2, or 3;        -   h represents 0, 1, or 2;

    -   4.4)

wherein

-   -   -   R¹²⁵ represents        -   4.4.a) H;        -   4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen;        -   4.4.d) —C(O)R¹²⁹ wherein            -   R¹²⁹ represents            -   4.4.d1) optionally substituted phenyl,            -   4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3                substituents independently selected from                -   4.4.d2.1) halogen; and                -   4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or                    (C₁-C₃)alkyl which may optionally bear halogen;            -   4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl; or            -   4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are                independently H or —(C₁-C₃)alkyl which may optionally                bear halogen; and        -   j represents 1, 2, or 3;

    -   4.5)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and

-   -   -   m represents 1, 2, or 3;

    -   4.6)

wherein

-   -   -   n represents 1, 2, or 3; and        -   p represents 0, 1, or 2;

    -   4.7)

wherein

-   -   -   q represents 1, 2, or 3;

    -   4.8)

wherein

-   -   -   R¹⁷⁸ represents        -   4.8.a) H;        -   4.8.b) —(C₁-C₃)alkyl which may optionally bear halogen;        -   4.8.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally            substituted phenyl or —(C₁-C₃)alkyl which may optionally            bear up to 3 substituents independently selected from            -   4.8.d1) halogen; and            -   4.8.d4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl                which may optionally bear halogen;        -   4.8e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl; or        -   4.8.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each            independently represents H or —(C₁-C₃)alkyl which may            optionally bear halogen;        -   r represents 0, 1, or 2; and        -   s represents 0 or 1;

-   or a pharmaceutically acceptable salt thereof.

In a distinct embodiment, the present invention encompasses a compoundhaving the formula:

-   -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-tert-butylisoxazol-5-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl3urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-(3-tert-butylisoxazol-5-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[3-(trifluoromethoxy)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methoxyphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methoxyphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-tert-butyl-2-methoxyphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2,5-dimethylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-methylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-methylphenyl)urea        hydrochloride;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-tert-butylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-ethylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(4-tert-butylpyridin-2-yl)urea;.    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-fluoropyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[5-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-methylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea;    -   N-(3-acetylphenyl)-N′-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}urea        trifluoroacetate;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3,4-dimethylphenyl)urea        trifluoroacetate;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3,5-dimethylphenyl)urea        trifluoroacetate;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-chloro-4-methylphenyl)urea        trifluoroacetate;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-chloropyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-chlorophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-bromophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-methoxypyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-ethylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(6-methoxypyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(6-bromopyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-phenoxyphenyl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-ethylphenyl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-methylphenyl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl        4-[(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate;    -   N-{4-[amino-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl        4-[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate;    -   N-[4-(4-amino-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-{[4-(ethylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-{[4-(isopropylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-({4-[(2,2,2-trifluoroethyl)sulfonyl]piperazin-1-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(5-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}pyridin-2-yl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl        4-({4-amino-5-[4-({[(6-bromopyridin-2-yl)amino]carbonyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}methyl)piperazine-1-carboxylate;    -   N-{4-[4-amino-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea;    -   N-(4-{4-amino-7-[(4-isopropylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-(6-bromopyridin-2-yl)urea;    -   N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-(6-bromopyridin-2-yl)urea;    -   N-[4-(4-amino-7-{[4-(methylsulfonyl)piperazin-1-yl)methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea;    -   N-[4-(4-amino-7-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea;    -   4-amino-N-(2,2,2-trifluoroethyl)-5-{4-[(}[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;    -   4-amino-N-(tert-butyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;    -   N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea;    -   N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea;    -   N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylacetyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-hydroxy-1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea;    -   N-[4-(4-amino-7-{[(2,2,2-trifluoroethyl)amino]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl        4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate;    -   N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(trifluoroacetyl)piperidin-4-yl]pyrrolo[2,1-][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(fluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[7-(1-allylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   ethyl        [4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]acetate;    -   [4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]acetic        acid;    -   2-[4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]-N-methylacetamide;    -   N-(4-{4-amino-7-[1-(2,3-dihydroxypropyl)piperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   4-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-ethylpiperidine-1-carboxamide;    -   4-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-tert-butylpiperidine-1-carboxamide;    -   4-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-isopropylpiperidine-1-carboxamide;    -   N-{-[4-amino-7-(morphlin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-bromophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-chlorophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-methoxyphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(4-methylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-chlorophenyl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(4-methylpyridin-2-yl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea;    -   N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3,4-dichlorophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-chlorophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-(3-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3,4-dichlorophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-tert-butylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-ethylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-fluorophenyl}-N′-(3-ethylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3,4-dichlorophenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3,5-dimethylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-methylphenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-fluorophenyl}-N′-(4-fluoro-3-methylphenyl)urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-ethylphenyl)urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-3-(2-fluoro-5-methylphenyl)urea;    -   1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-(2-fluoro-5-methylphenyl)urea;    -   N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoroethyl)phenyl]urea;    -   N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,5-difluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-pyrrolidin-1-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[3-(4-methylpiperazin-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{7-[3-(4-acetylpiperazin-1-yl)propyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(fluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   1-{4-[4-amino-7-(3-hydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[3-(1,4-oxazepan-4-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[3-(dimethylamino)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[3-(3-oxopiperazin-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-thiomorpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-{3-[ethyl(2-hydroxyethyl)amino]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl        3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate;    -   tert-butyl        3-{4-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate;    -   1-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-(4-{4-amino-7-[1-(methylsulfonyl)pyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N,N-dimethylpyrrolidine-1-carboxamide;    -   1-{4-[4-amino-7-(1-glycoloylpyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   1-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl        3-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate;    -   4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-methylpiperidine-1-carboxamide;    -   4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N,N-dimethylpiperidine-1-carboxamide;    -   N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(2-morpholinylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[2-(dimethylamino)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[2-(4-methylpiperazin-1-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-{2-[2-(methoxymethyl)pyrrolidin-1-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(2-pyrrolidin-1-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(4-morpholin-4-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[2-(1,4-oxazepan-4-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(1-lactoylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(cyclopropylcarbonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-glycoloylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[1-(cyclopropylcarbonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[1-(N,N-dimethylglycyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2-ethoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2-ethoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   4-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide;    -   N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   1-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(1-hydroxyprop-2-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,2-dihydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1,2,3-trihydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   2-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-oxoethyl        acetate;    -   N-{4-[4-amino-7-(bromoacetyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(3-morpholin-4-ylpropoxy)acetyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[(2-morpholin-4-ylethoxy)acetyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(1-cyclopropylpipeidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   tert-butyl-4-(4-amino-5-{3-chloro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate;    -   N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-chlorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-(trifluoromethyl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea;    -   tert-butyl-4-(4-amino-5-{3-fluoro-4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate;    -   N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   tert-butyl-4-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino        }carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate;    -   N-{4-[4-amino-7-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   tert-butyl(4-amino-5-{2,5-difluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate;    -   N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,5-difluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-(trifluoromethoxy)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-(4-tert-butylpyridin-2-yl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-(2-fluoro-5-methylphenyl)urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   tert-butyl-2-({[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate;    -   4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;    -   N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-2-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;    -   N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea;    -   4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]aminocarbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7carboxamide;    -   4-amino-5-{3-fluoro-4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;    -   4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;    -   4-amino-5-{2,5-difluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide;    -   1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;    -   1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea;    -   N-{4-[4-amino-7-(morpholin-2-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   N-{4-[4-amino-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;    -   or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides acompound having the formula:

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea;

N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[(trifluoromethyl)pyridin-2-yl]urea;

N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f]1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][(1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

[4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]aceticacid;

2-[4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]-N-methylacetamide;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea;

N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-fluoro-3-methylphenyl)urea;

N-{4-[amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

1-{4-[4-amino-7-(1-glycoloylpyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea;

4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-methylpiperidine-1-carboxamide;

N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1-glycoloylpiperidinyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea;

N-{4-[4-amino-7-(1-glycoloylpiperidinyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea;

N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea;

or a pharmaceutically acceptable salt thereof.

Definitions

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric center, and diastereomeric mixtures in the case ofmultiple asymmetric centers. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Substituents on a ring may also be present in either cis ortrans form. It is intended that all such configurations (includingenantiomers and diastereomers), are included within the scope of thepresent invention. Preferred compounds are those which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic or diastereomeric mixtures of thecompounds of this invention are also included within the scope of thepresent invention. The purification and the separation of such materialscan be accomplished by standard techniques known in the art. The opticalisomers can be obtained by resolution of the racemic mixtures accordingto conventional processes, for example, by the formation ofdiastereoisomeric salts using an optically active acid or base orformation of covalent diastereomers. Examples of appropriate acids aretartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.Mixtures of diastereoisomers can be separated into their individualdiastereomers on the basis of their physical and/or chemical differencesby methods known in the art, for example, by chromatography orfractional crystallization. The optically active bases or acids are thenliberated from the separated diastereomeric salts. A different processfor separation of optical isomers involves the use of chiralchromatography (e.g., chiral BPLC columns), with or without conventionalderivitization, optimally chosen to maximize the separation of theenantiomers. Suitable chiral HPLC columns are manufactured by Diacel,e.g., Chiracel OD and Chiracel OJ among many others, all routinelyselectable. Enzymatic separations, with or without derivitization, arealso useful. The optically active compounds of this invention canlikewise be obtained by chiral syntheses utilizing optically activestarting materials.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts,co-precipitates, metabolites, hydrates, solvates and prodrugs of all thecompounds of examples. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic acid additionsalt of a compound of the present invention. For example, see S. M.Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, magnesium, ammonium, and chlorine salts.Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

The term “solvates” for the purposes of the invention are those forms ofthe compounds that coordinate with solvent molecules to form a complexin the solid or liquid state. Hydrates are a specific form of solvates,wherein the solvent is water.

The term “alkyl” refers to a straight-chain or branched saturatedhydrocarbon radical having generally 1 to 6, 1 to 4 or 1 to 3 carbonatoms, illustratively representing methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

The term “cycloalkyl” refers to saturatated carbocyclic groups.Preferred cycloalkyl groups include C₃-C₆ rings, illustrativelyrepresenting cyclopropyl, cyclopentyl, and cyclohexyl.

The term “alkoxy” refers to a straight-chain or branched hydrocarbonradical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms and bound via anoxygen atom, illustratively representing methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy.The terms “alkoxy” and “alkyloxy” are often used synonymously. The term“alkylamino” refers to an amino radical having one or two (independentlyselected) alkyl substituents, illustratively representing methylamino,ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

The term “alkylaminocarbonyl” refers to an alkylaminocarbonyl radicalhaving one or two (independently selected) alkyl substituents,illustratively representing methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl,n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl,N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl,N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino-carbonyl andN-n-hexyl-N-methylaminocarbonyl.

The term “alkylaminosulfonyl” refers to an aminosulfonyl radical havingone or two (independently selected), alkyl substitutents on the aminomoiety, illustratively representing methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexyl-aminosulfonyl,N,N-dimethylaminosulfonyl, N,N-diethylaminosulfonyl,N-ethyl-N-methylaminosulfonyl, N-methyl-N-n-propylaminosulfonyl,N-isopropyl-N-n-propylaminosulfonyl, N-t-butyl-N-methylaminosulfonyl,N-ethyl-N-n-pentylaminosulfonyl and N-n-hexyl-N-methylaminosulfonyl.

The term “alkylsulfonylamino” refers to a sulfonylamino radical havingan alkyl substitutent on the sulfonylamino moiety, illustrativelyrepresenting methylsulfonylamino, ethylsulfonylamino,n-propylsulfonylamino, isopropylsulfonylamino, tert-butyl-sulfonylamino,n-pentylsulfonylamino and n-hexylsulfonylamino.

The term “alkoxycarbonyl” refers to a carbonyl radical being substitutedwith an alkoxy radical, illustratively representing methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

The term “alkoxycarbonylamino” refers to a carbonylamino radical beingsubstituted with an alkoxy radical on the carbonyl moiety,illustratively representing methoxycarbonylamino, ethoxycarbonylamino,n-propoxycarbonylamino, isopropoxycarbonylamino,tert-butoxycarbonylamino, n-pentoxycarbonylamino andn-hexoxycarbonylamino.

The term “heteroaryl” refers to a mono- or bicyclic radical having 5 to10 or 5 or 6 ring atoms and up to 4 hetero atoms selected from the groupconsisting of nitrogen, oxygen and sulfur, which is aromatic at least inone ring. It can be attached via a ring carbon atom or a ring nitrogenatom. If it represents a bicycle, wherein one ring is aromatic and theother one is not, it can be attached at either ring. Illustrativeexamples of such groups are the thiophene, furan, pyrrole, thiazole,oxazole, imidazole, pyridine, pyrimidine, pyridazine, indole, indazole,benzofuran, benzothiophene, quinoline and isoquinoline groups.

Language reciting a 5-6 membered aromatic heterocycle containing up to 3heteroatoms independently selected from the group consisting of N, O,and S is meant to refer to aromatic heterocycles such as furan,thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole,isothiazole, imidaxole, an oxadiazole, 1,3,2-dioxazole,1,2,5-oxathiazole, 1,2-pyrone, 1,4-pyrone, pyridine, pyridazine,pyrimidine, pyrazine, a triazine, o- and p-isoxazines,1,2,5-oxathiazine, 1,2,4-oxadiazine, and the like.

Language reciting a bicyclic heterocycle of 8-10 ring members in whichat least one ring is aromatic and contains up to 3 moietiesindependently selected from the group consisting of N, N→O, O, and S,and any non-aromatic ring of said bicyclic heterocycle optionallycontains up to three moieties independently selected from the groupconsisting of O, S, S(O), S(O)₂, and NR, is meant to refer to bicyclicheterocycles in which at least one ring is a 5-6-membered aromaticheterocycle as discussed above, which is fused to a second ring whichmay be aromatic or nonaromatic. Where this second ring is aromatic, itmay also optionally contain up to 3 moieties independently selected fromthe group consisting of N, N→O, O, and S, and where this second ring isnonaromatic, it may optionally contain up to three moietiesindependently selected from O, S, S(O), S(O)₂, and NR.

The term “heterocyclyl” refers to a saturated or partially unsaturatedmono- or bicyclic heterocyclic ring which contains 3 to 8 or 5 to 6 ringatoms and 1 to 3 heteroatoms or hetero groups selected independentlyfrom the group consisting of nitrogen, oxygen and sulfur, CO, SO andSO₂, such as tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrrolinyl, piperidinyl, morpholinyl, or perhydroazepinyl. It can beattached via a ring carbon atom or a ring nitrogen atom.

The terms “halo” and “halogen” refer to fluorine, chlorine, bromine oriodine.

A bicyclic carbocycle of 9-10 ring members in which at least one ring isaromatic is a compound such as indene, isoindene, andtetrahydronaphthalene.

Language stating that an alkyl or alkoxy group may optionally bearhalogen or may be substituted with halogen means that the group may bearone or more halogens, up to perhalo.

Language reciting that in a group —NRR, the two R groups may be joinedand taken together with the N atom to which they are attached form a 5-6membered ring which may optionally contain a ring member selected fromO, S, and NR^(x) wherein R^(x) represents H or (C₁-C₃)alkyl, is meant toindicate formation of groups such as pyrrolidine, imidazolidine,piperidine piperazine, morpholine, thiomorpholine, and the like.

Language indicating that two substituent groups of a tertiary aminomoiety may be joined and taken together with the N to which they areattached form an aromatic or nonaromatic 5-6 membered ring which mayoptionally contain a ring member selected from O, S, and NR is meant toindicate the possibility of forming 5-6-membered N-containingheterocycles such as pyrrole, pyrazole, piperazine, morpholine,piperidine, imidazole, pyrrolidine, imidazolidene, and the like.

When NR is indicated as being part of a heterocycle, this means that theN atom is the ring member and R is a substituent.

Language reciting a 5-6 membered heteroaromatic containing up to twoheteroatoms selected from O, S, and N is meant to refer to groups suchas furan, thiophene, pyrrole, pyrazole, oxazole, isoxazole, thiazole,isothiazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine,isoxazine, and the like.

The term “aryl” refers to a mono- to tricyclic carbocyclic radical,which is aromatic at least in one ring, having generally 6 to 14 carbonatoms, illustratively representing phenyl, naphthyl and phenanthrenyl.

The term “substituted phenyl” refers to an phenyl radical having one ormore (but typically not more than three) groups independently selectedfrom halogen; alkyl such as (C₁-C₃)alkyl; alkoxy such as O(C₁-C₃)alkyl;CN; cycloalkyl; heteroaryl; heterocyclyl; amino; alkylamino such asmono- or di-(C₁-C₃)alkylamino; acylamino wherein for example the acylgroup is —C(O)(C₁-C₃)alkyl or —C(O)phenyl alkoxycarbonyl; CN; NO₂;alkynyl; alkenyl; C(O)NH₂; —C(O)NH(C₁-C₃)alkyl; C(O)N((C₁-C₃)alkyl)₂;C(O)NH-phenyl; —NHC(O)NH₂ ; alkylaminosulfonyl; alkylsulfonylamino; andalkoxycarbonylamino, and in these groups, alkyl and phenyl groups may befurther substituted with halogen.

Language stating that phenyl may be optionally substituted with halogenmeans that the phenyl group optionally may bear one or more substituentsindependently selected from fluorine, chlorine, bromine and iodine, upto a maximum of perhalo, but typically not more than three such groups.

Language stating that a cycloalkyl group may optionally bear halogen oralkoxy is meant to indicate that the cycloalkyl group may be bear one ormore halogen substituents, up to perhalo, and/or it may bear one or morealkoxy groups, generally up to a maximum of three.

The skilled in the art understand that when two heteroatoms are attachedto a single aliphatic carbon atom, the resulting material is usually notstable. Accordingly, in this invention, when an aliphatic group bearstwo heteroatom-containing substituents (such as amino and alkoxy, forexample) in which the heteroatoms are joined to the aliphatic group,such heteroatom-containing substituents will generally need to belocated on different carbon atoms of the aliphatic material.

A wavy line across the end of a line which indicates a chemical bondextending from a chemical substructure or functional group means thatthe substructure or group is attached to the remainder of the moleculevia that bond.

A carbonyl group is indicated as C═O in a chemical structure orsubstructure, or by C(O) in a typed formula.

In naming a multiunit functional group by listing the constituent units,the terminal unit is recited first, then the adjacent unit is recited,etc. An example of this style of nomenclature would be “alkylphenyl”,which connotes an alkyl group located on a phenyl group, which is inturn connected to the remainder of the molecule. Conversely, the term“phenylalkyl” would connote a phenyl group located on an alkyl groupwhich is in turn connected to the remainder of the molecule. Anotherexample would be “cycloalkylalkyl”, which connotes a cycloalkyl groupconnected to an alkyl group which is in turn connected to the remainderof the molecule.

In this document, for the sake of simplicity, the names of substituentgroups are generally (but not always) given as names of the parentcompounds rather than using nomenclature which indicates their status assubstituents. Thus, for example, if a substituent in a compound of theinvention were a pyridine ring, it would generally be termed a“pyridine” substituent rather than a being referred to as a “pyridyl”group. Where the nomenclature indicating status as a substituent is notemployed, and a substituent is named in terms of its parent, its statusas a substituent will be clear from the context.

Salts of the compounds identified herein can be obtained by isolatingthe compounds as hydrochloride salts, prepared by treatment of the freebase with anhydrous HCl in a suitable solvent such as THF. Generally, adesired salt of a compound of this invention can be prepared in situduring the final isolation and purification of a compound by means wellknown in the art. Or, a desired salt can be prepared by separatelyreacting the purified compound in its free base form with a suitableorganic or inorganic acid and isolating the salt thus formed. Thesemethods are conventional and would be readily apparent to one skilled inthe art.

If used as active compounds, the compounds according to the inventionare preferably isolated in more or less pure form, that is more or lessfree from residues from the synthetic procedure. The degree of puritycan be determined by methods known to the chemist or pharmacist (seeespecially Remington's Pharmaceutical Sciences, 18^(th) ed. 1990, MackPublishing Group, Enolo). Preferably the compounds are greater than 99%pure (w/w), while purities of greater than 95%, 90% or 85% can beemployed if necessary.

Throughout this document, for the sake of simplicity, the use ofsingular language is given preference over plural language, but isgenerally meant to include the plural language if not otherwise stated.E.g., the expression “A method of treating a disease in a patient,comprising administering to a patient an effective amount of a compoundof claim 1” is meant to include the simultaneous treatment of more thanone disease as well as the administration of more than one compound ofclaim 1.

The compounds according to the invention exhibit an unforeseeable,useful pharmacological and pharmacokinetic activity spectrum. They aretherefore suitable for use as medicaments for the treatment and/orprophylaxis of disorders in humans and animals.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilized to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadecaethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyarethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma. Examples of liver cancers include, but are not limitedto hepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancersinclude, but are not limited to squamous cell carcinoma, Kaposi'ssarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanomaskin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant kinase activity (such as tyrosinekinase activity), including, FGFR1, FGFR2, FGFR3, FGFR4, VEGFR1, VEGFR2,VEGFR3, Tie2, PDGFR, Aurora A, Aurora B, EphB4, EphA2, p70S6K, RSK,TrkA, Trk B, RET, Src, c-Yes and Fyn.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of FGFR1, FGFR2, FGFR3, FGFR4, VEGFR1, VEGFR2,VEGFR3, Tie2, PDGFR, Aurora A, Aurora B, EphB4, EphA2, p70S6K, RSK,TrkA, Trk B, RET, Src, c-Yes and Fyn comprising administering aneffective amount of a compound of the present invention, includingsalts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.:esters) thereof, and diastereoisomeric forms thereof. Kinase activitycan be inhibited in cells (e.g., in vitro), or in the cells of amammalian subject, especially a human patient in need of treatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855),neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof.

The additional pharmaceutical agent can be aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BCG or tice BCG, bestatin, betamethasone acetate,betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, levothroid, levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargraimostim, semustine,sizofiran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin,CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafamib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Experimental Abbreviations and Acronyms

A comprehensive list of the abbreviations used by organic chemists ofordinary skill in the art appears in The ACS Style Guide (third edition)or the Guidelines for Authors for the Journal of Organic Chemistry. Theabbreviations contained in said lists, and all abbreviations utilized byorganic chemists of ordinary skill in the art are hereby incorporated byreference. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughoutthis disclosure, they have the following meanings:

Abbreviations and Acronyms

-   ^(t)H-NMR proton nuclear magnetic resonance spectroscopy-   ³¹P-NMR phophorus-31 nuclear magnetic resonance spectroscopy-   AcOH acetic acid-   (Ac)₂O acetic anhydride-   abs absolute-   aq aqueous-   ap approximate-   atm atmosphere-   br broad-   BOP benzotriazole-1-yloxy-tris(dimethylamino)phosphonium    hexafluorophosphate-   Bu butyl-   ACN acetonitrile-   Ac₂O acetic anhydride-   AcOH acetic acid-   Celite® brand of diatomaceous earth from Celite Corp.-   CD₃CN acetonitrile-d₃-   CD₃OD methanol-d₄-   d doublet-   DCE dichloroethane-   DCM dichloromethane-   dd double doublet-   DIBAL diisobutylaluminum hydride-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d₆ dimethyldsulfoxide-d₆-   equiv equivalent(s)-   ES-MS electrospray mass spectrometry-   Et₃N triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   FBS fetal bovine serum-   g gram(s)-   h hour(s)-   Hex Hexanes-   HPLC high performance liquid chromatography-   Hz hertz-   J NMR coupling constant-   KOAc Potassium Acetate-   L liter(s)-   LCMS liquid chromatography-mass spectrometry-   LHMDS lithium hexamethyldisilazide-   M molar-   mCPBA meta-Chloroperoxybenzoic acid-   Me methyl-   MeOH methanol-   mg milligram(s)-   MHz megahertz-   min minute(s)-   mL milliliter-   mmol millimole-   MPLC medium pressure liquid chromatography-   MS mass spectrometry-   Ms methanesulfonyl-   N normal-   nM nanomolar-   Pr propyl-   py-BOP benzotriazol-1-yl-oxytripyrrolidineophosponium    hexafluorophosphate-   q quartet-   Ra-Ni Raney-Nickel-   R_(f) TLC retention factor-   Rochelle's potassium sodium tartrate salt-   RPMI Roswell Park Memorial Institute-   RT retention time-   rt room temperature-   s singlet-   satd. saturated-   t triplet-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TosMIC Tosylmethyl isocyanide-   TPP triphenylphosphine-   Ts p-toluenesulfonyl-   v/v volume-to-volume proportion-   v/v/v volume-to-volume-to-volume proportion-   μL microliter-   μm micrometer

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated under reduced pressure” refers touse of a Buchi rotary evaporator at approximately 15 mm of Hg. Alltemperatures are reported uncorrected in degrees Celsius (° C.). Thinlayer chromatography (TLC) was performed on pre-coated glass-backedsilica gel 60 A F-254 250 μm plates.

The structures of compounds of this invention were confirmed using oneor more of the following procedures.

NMR

NMR spectra were acquired for each compound and were consistent with thestructures shown.

Routine one-dimensional NMR spectroscopy was performed on either 300 or400 MHz Varian® Mercury-plus spectrometers. The samples were dissolvedin deuterated solvents. Chemical shifts were recorded on the ppm scaleand were referenced to the appropriate solvent signals, such as 2.49 ppmfor DMSO-d6, 1.93 ppm for CD3CN, 3.30 ppm for CD3OD, 5.32 ppm for CD2Cl2and 7.26 ppm for CDCl3 for 1H spectra.

GC/MS

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5973 mass spectrometer equipped Hewlett Packard 6890 Gas.Chromatograph with a J & W HP-5 column (0.25 uM coating; 30 m×0.32 mm).The ion source was maintained at 250° C. and spectra were scanned from50-550 amu at 0.34 sec per scan.

LC/MS

Unless otherwise noted, all retention times are obtained from the LC/MSand correspond to the molecular ion. High pressure liquidchromatography-electrospray mass spectra (LC/MS) were obtained using oneof the following:

Method A (LCQ)

Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector set at 254 nm, a Waters Sunfire C18 column (2.1×30mm, 3.5 □m), a Gilson autosampler and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-1200 amu using a variable ion time according to the number of ionsin the source. The eluents were A: 2% acetonitrile in water with 0.02%TFA, and B: 2% water in acetonirile with 0.018% TFA. Gradient elutionfrom 10% B to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min wasused with an initial hold of 0.5 minutes and a final hold at 95% B of0.5 minutes. Total run time was 6.5 minutes.

Method B (LCQ5)

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, a variable wavelengthdetector set at 254 nm. The HPLC column used was a Waters Sunfire C-18column (2.1×30 mm, 3.5 μm). The HPLC eluent was directly coupled withoutsplitting to a Finnigan LCQ DECA ion trap mass spectrometer withelectrospray ionization. Spectra were scanned from 140-1200 amu using avariable ion time according to the number of ions in the source usingpositive ion mode. The eluents were A: 2% acetonitrile in water with0.02% TFA, and B: 2% water in acetonirile with 0.02% TFA. Gradientelution from 10% B to 90% 13 over 3.0 minutes at a flow rate of 1.0mL/min was used with an initial hold of 1.0 minutes and a final hold at95% B of 1.0 minutes. Total run time was 7.0 minutes.

Method C (LTQ)

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, and a diode array. TheHPLC column used was a Waters Sunfire C18 column (2.1×30 mm, 3.5 μm).The HPLC eluent was directly coupled with a 1:4 split to a Finnigan LTQion trap mass spectrometer with electrospray ionization. Spectra werescanned from 50-800 amu using a variable ion time according to thenumber of ions in the source using positive or negative ion mode. Theeluents were A: water with 0.1 formic acid, and B: acetonitrile with0.1% formic acid. Gradient elution from 10% B to 90% B over 3.0 minutesat a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutesand a final hold at 95% B of 1.0 minutes. Total run time was 8.0minutes.

Method D

Gilson HPLC system equipped with a variable wavelength detector set at254 nm, a YMC pro C-18 column (2×23 mm, 120 A), and a Finnigan LCQ iontrap mass spectrometer with electrospray ionization. Spectra werescanned from 120-1200 amu using a variable ion time according to thenumber of ions in the source. The eluants were A: 2% acetonitrile inwater with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA.Gradient elution from 10% B to 95% over 3.5 minutes at a flow rate of1.0 mL/min was used with an initial hold of 0.5 minutes and a fmal holdat 95% B of 0.5 minutes. Total run time was 6.5 minutes.

Method E

Agilent 1100 HPLC system. The Agilent 1100 HPLC system was equipped withan Agilent 1100 autosampler, quaternary pump, and a diode array. TheHPLC column used was a Waters Sunfire (2.1×30 mm, 3.5 μm). The HPLCeluent was directly coupled with a 1:4 split to a Finnigan LTQ ion trapmass spectrometer with electrospray ionization. Spectra were scannedfrom 50-1000 amu using a variable ion time according to the number ofions in the source in either positive or negative ion mode. The eluentswere A: water with 0.1 formic acid, and B: acetonitrile with 0.1% formicacid. Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 2.0 minutes and afinal hold at 95% B of 1.0 minutes. Total run time was 8.0 minutes.

Preparative HPLC:

Preparative HPLC was carried out in reversed phase mode, typically usinga Gilson HPLC system equipped with two Gilson 322 pumps, a Gilson 215Autosampler, a Gilson diode array detector, and a C-18 column (e.g. YMCPro 20×150 mm, 120 A). Gradient elution was used with solvent A as waterwith 0.1% TFA, and solvent B as acetonitrile with 0.1% TFA. Followinginjection onto the column as a solution, the compound was typicallyeluted with a mixed solvent gradient, such as 10-90% Solvent B inSolvent A over 15 minutes with flow rate of 25 mL/min. The fraction(s)containing the desired product were collected by UV monitoring at 254 or220 nm.

Preparative MPLC:

Preparative medium pressure liquid chromatography (MPLC) was carried outby standard silica gel “flash chromatography” techniques (e.g., Still,W. C. et al. J. Org. Chem. 1978, 43, 2923-5), or by using silica gelcartridges and devices such as the Biotage Flash systems. A variety ofeluting solvents were used, as described in the experimental protocols.

General Preparative Methods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below, and the preparation ofrepresentative compounds is specifically illustrated in examples.

Synthetic transformations that may be employed in the synthesis ofcompounds of this invention and in the synthesis of intermediatesinvolved in the synthesis of compounds of this invention are known by oraccessible to one skilled in the art. Collections of synthetictransformations may be found in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York    (1992)-   R. C. Larock. Comprehensive Organic Transformations, 2nd ed.;    Wiley-VCH: New York (1999)-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;    Plenum Press: New York (1984)-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3rd ed.; John Wiley: New York (1999)-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2nd ed.; University Science Books: Mill Valley, Calif.    (1994)-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994)-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional Group Transformations; Pergamon Press: Oxford, UK    (1995)-   G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991)-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984)-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)-   C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal    Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSyntheses; John Wiley: New York; Reagents for Organic Synthesis: JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley:New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSciFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

Methods for preparing pyrrolotriazines are also disclosed in publishedU.S. application Ser. No. 10/289,010 (Publication No. US 2003-0186982A1), U.S. Pat. No. 6,670,357 (U.S. application Ser. No. 10/036,293), aswell as WO 2003/042172, WO 2004/009542, WO2004/009601, WO 2004/009784,WO 2004/013145 and WO 2005/121147 all of which are hereby incorporatedby reference in their entirety.

General Methods of Preparation of Invention Compounds

It is also to be understood that starting materials are commerciallyavailable or readily prepared by standard methods well known in the art.Such methods include, but are not limited to the transformations listedherein.

If not mentioned otherwise, the reactions are usually carried out ininert organic solvents which do not change under the reactionconditions. These include ethers, such as diethyl ether, 1,4-dioxane ortetrahydrofuran, halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, 1,2-dichloroethane,trichloroethane or tetrachloroethane, hydrocarbons, such as benzene,toluene, xylene, hexane, cyclohexane or mineral oil fractions, alcohols,such as methanol, ethanol or iso-propanol, nitromethane,dimethylformamide or acetonitrile. It is also possible to use mixturesof the solvents.

The reactions are generally carried out in a temperature range of from0° C. to 150° C., preferably from 0° C. to 70° C. The reactions can becarried out under atmospheric, elevated or under reduced pressure (forexample from 0.5 to 5 bar). In general, they are carried out underatmospheric pressure of air or inert gas, typically nitrogen.

Compounds of the present invention of formula I can be prepared bystraightforward means as described in the reaction schemes below or bymeans well known to those skilled in the art. In these reaction schemes,unless otherwise specifically defined, the meanings of R¹, R², R³, R⁴and X⁰ are identical to those described above.

Reaction Scheme 1 illustrates a general method of preparing compounds offormula I from the corresponding bromo compounds of formula 1-3 bymethods of cross coupling (Suzuki) that are well known in the art. Thus,coupling bromide of formula 1-1 with the appropriately substitutedboronate (G¹=C(O)NHR¹) of formula 1-2 to furnish compounds of formula Idirectly. Alternatively, coupling bromide of formula 1-1 with theappropriately substituted boronate (G¹=H, PG; where PG is an optionalprotecting group known in the art) lead to anilines of formulas 1-3. and1-4. If necessary, the protecting group (PG) can be removed first bymethods well known in the art (e.g. acid catalyzed removal of BOCcarbamates). The reaction of anilines of formula 1-4 with either anisocyanate of formula 1-5 or carbamate of formula 1-6, generally in aninert solvent, provides compounds of formula I directly.

Reaction Scheme 2 outlines a method for preparing substituted boronatesof formula 1-2, starting from bromides of formula 2-1. Thus, reactionsof 2-1 with bis(pincolato)diboron under coupling conditions well knownin the art (Step A) will provide boronates of formula 1-2 (G¹=H)directly. Alternatively, treatment of anilines of formula 2-1isocyanates or cabamates under conditions described in Scheme 1 willprovide bromides of formula 2-2 (G¹=C(O)NHR¹). Additionally anilines offormula 2-1 can be protected with an appropriate group (G¹=PG), whichcan be synthesized under conditions well know in the art. Boronates offormula 1-2 (G¹=PG, C(O)NHR′) can be generated from the correspondingbromides of formula 2-2 under the conditions given in Step A. Ifnecessary boronates of formula 1-2 (G¹=H) can be further transformedinto boronates of formula 1-2 (G¹=PG, C(O)NHR¹) by the conditionsoutlined in step B.

Reaction Scheme 3 describes the preparation of common intermediates 3-5,3-6, and 3-7 from a common precursor 3-4. Common intermediates 3-5, 3-6and 3-7 are useful precursors to ones skilled in the art towardgeneration of diversity at R⁴. Treatment of commercially available2,5-dialkoxy tetrahydrofuran (3-1) with a protected hydrazine underacidic conditions provides the n-substituted amino pyrrole 3-2.Cyanation at the 2-position is easily effected by treatment withreagents such chlorosulphonyl isocyanate. The protecting group (PG) canthen be removed by methods well know in the art (e.g. HCl in an aproticsolvent for the removal of a BOC carbamate) to provide intermediate 3-3.Cyclization of 3-3 can be affected by treatment with a formamidingderivative such as formamidine acetate or the like in a solvent such asEtOH to provide the pyrrolotriazine intermediate of formula 3-4.Differentiation can be effected by the regioselective electrophilicaddition of various functional groups at the 7-position of formula 3-4.Treatment of compounds of 3-4 under Mannich conditions, such as bytreatment with an amine, such as a primary or secondary (cyclic oracyclic) amine, and formaldehyde and the like in a solvent such asacetic acid or the like provide compounds of formula 3-5. Compounds offormula 3-6 can be prepared directly from compounds of formula 3-4 usinga lewis acid such as AlCl₃ and the like and an acid chloride such asacetyl chloride and the like. Bromination of 3-4 with reagents such as1,3-dibromo-5,5-dimethylhydantoin or other brominating agent in anappropriate solvent, such as DMF or the like, provides 3-7

Reaction Scheme 4 outlines some of the ways in which common intermediate3-7 can be utilized to provide functionality at the R⁴ position. Halogenmetal exchange on common intermediate 3-7 with an appropriateorganometallic reagent, such as n-butyl lithium and the like, in aninert solvent (eg. TV) provides the transient species 4-1, which can bequenched with a variety of electrophiles that are well known in the art.Treatment of 4-1 with reagents such as DMF and the like providesaldehyde intermediate 4-2. Treatment of 4-1 with CO₂ provides acidintermediate 4-3. Treatment of 4-1 with reagents such as ethylene oxideand the like provides alcohol intermediate 4-3. Treatment of 4-1 withreagents such as Weinreb amides such as compounds of formula 4-6provides substituted ketones of formula 4-5.

Reaction Scheme 5 outlines some additional of the ways in whichfunctionality at the R⁴ position can be introduced and modified throughcommon intermediate 3-7. Metal insertion into 3-7 with an appropriatemetal (e.g. palladium, nickel, zinc and the like), provides thetransient species 5-1, which can be coupled with a variety of reagentsfamiliar to those skilled in the art. Treatment of 5-1 with vinylboronates or boronic acids such as 5-2 or 5-5 under conditions that arewell known in the art and provides the appropriately protectedintermediates 5-3 and 5-7 respectively. Alternatively, 5-1 can betreated with alkynes of formula 5-4 in presence of a Pd(II) catalyst, aCu(I) co-catalyst and an amine base such as pyrrolidine or triethylamineor the like, in a solvent such as DMF or the like to provide compoundsof formula 5-6. Intermediate 5-1 can also be treated with alcohols undera carbon monoxide atmosphere to provide intermediates of formula 5-8.

Reaction Scheme 6 describes the preparation of compounds of formula 6-3,where G² is defined as a subset of R⁴ including intermediates describein Schemes 3, 4, and 5. Thus, treatment of compounds of formula 6-1 witha brominating reagent such as 1,3-dibromo-5,5-dimethylhydantoin or thelike in an appropriate solvent, such as THF or the like, providescompounds of formula 6-2. A metal mediated cross coupling such as Suzukior the like under conditions well known in the art provide compounds ofthe formula 6-3. Compounds of formula 6-3 can be formula I.Alternatively, in compounds of formula 6-3 G² can be further elaboratedas described in Schemes 7-12 to provide R⁴.

Reaction Scheme 7 describes some of the ways the aldehyde functionalgroup in compounds of formula 7-1 can be manipulated, where G³ isdefined in Scheme 7 and G¹ is defined in Scheme 1. Thus, compounds offormula 7-2 can be prepared by ones skilled in the art by treatment withan amine, such as a primary or secondary (cyclic or acyclic) amine, inthe presence of a suitable reducing agent, such as sodiumtriacetoxyborohydride or the like in a suitable solvent such asdichloroethane or the like. Alternatively, compounds of formula 7-1 canbe treated with a Grignard reagent or the like, in an appropriatesolvent such as THF or the like provides alcohols of formula 7-3.Cyclized compounds of formula 7-4 can also be synthesized by treatmentof 7-1 with isocyanide reagents (eg. TosMIC and the like). Thus,treatment of compounds of formula 7-1 with a reducing agent, preferablyDIBAL-H, in a solvent such as THF or the like will provide primaryalcohols of formula 7-5. Halogenation of 7-5 with a reagent such asthionyl chloride or the like in a suitable solvent such as CH₂Cl₂provides α-halo compounds of formula 7-6 (X═Cl, Br or I). Treatment of7-6 with alcohols in a suitable solvent such as DMF or the like, in thepresence of a base such as Hυnigs base or the like and optionally with acatalyst such as potassium iodide or the like provides ethers of formula7-7. Alternatively, treatment of 7-6 with with an amine, such as aprimary or secondary (cyclic or acyclic) amine, in the presence of asuitable base, such as Hunigs base or the like provides compounds ofstructure 7-2.

Reaction Scheme 8 describes some of the ways the ketone functional groupin compounds of formula 8-1 can be manipulated, where G³ is defined inScheme 7. Thus, compounds of formula 8-1 can be treated with a reducingagent, such as DIBAL-H and the like in an appropriate solvent such asTHF and others, to provide secondary alcohols of the formula 8-3.Tertiary alcohols of formula 8-3 may also be generated by treatment of8-1 with Grignard reagents or the like in aprotic solvents such as THFand the like. Additionally, compounds of formula 8-1 can be treated witha silyl-triflate in the presence of a tertiary amine in solvents such asTHF to provide a silyl-enol ether. The compounds can be transformed intocompounds of formula 8-4 by treatment with a brominating agent such as1,3-dibromo-5,5-dimethylhydantoin or the like. The compounds of formula8-4 can be converted to compounds of formula 8-5 by treatment with anucleophile Nuc, wherein Nuc is defined as an amine, such as a primaryor secondary (cyclic or acyclic) amine, or as an alcohol or carboxylicacid, in a suitable solvent such as DMF or the like and optionally inthe presence of a catalyst such as potassium iodide and/or a base suchas potassium carbonate or the like. Optionally substituted heterocyclesof the formula 8-6 (Y can be independently N, O or S) can also begenerated by treatment of 8-4 with a variety of nucleophiles, which arewell known to those in the art (e.g. thioamides, or formamides for theformation of thiazoles and imidazoles respectively).

Reaction Scheme 9 describes some of the ways amides of formula 9-2 canbe synthesized, where G³ is defined in Scheme 7. Intermediate 9-1 can besynthesized by those experienced in the art by Scheme 4 or 5 and/orScheme 6. The carboxylic acid moiety can be synthesized directly fromintermediate 4-3 or from esters derived from intermediate 5-8, which canbe hydrolyzed under basic conditions (e.g. aqueous NaOH and the like) inan appropriate solvent. Coupling of compounds of formula 9-1 (carboxylicacids) with primary and secondary (cyclic or acyclic) amines underpeptide coupling conditions well known to those skilled in the artprovides amides of formula 9-2.

Reaction Scheme 10 describes the preparation of 10-4, which constitutesa subset of R⁴ wherein a primary or secondary (cyclic or acyclic) amineis connected by a 2, 3 or 4 carbon tether and G³ as defined in Scheme 7.Compounds of formula 10-1 contain either a alkene or alkyne moiety andcan exist as either the free alcohol or protected by a protecting group(PG) which is well known in the art. Hydrogenation of the alkene oralkyne of 10-1 in the presence of a catalyst such as PtO₂ or the likeprovides compounds of the formula 10-2 (n=2, 3). Alternatively,compounds of formula 10-2 (n=1) can be derived directly fromintermediate 4-4. If necessary the PG could be removed at this time byprocess well know in the art. Halogentaton of the resulting alcoholcould be effected with reagents well know in the art (e.g. carbontetrabromide and triphenylphosphine, or SOCl₂) in an aprotic solvent toafford compounds of the formula 10-3. Nucleophilic addition of a primaryor secondary (cyclic or acyclic) amine in a suitable solvent such as DMFor the like and optionally in the presence of a catalyst such aspotassium iodide and/or a base such as potassium carbonate or the likeprovides compounds of the formula 10-4.

Reaction Scheme 11 describes the preparation of compounds of formula11-3 (R⁴=unsubstituted piperidine or pyrollidine) or 11-4 (R⁵=optionallysubstituted piperidine or pyrollidine) wherein G³ is defined as above inScheme 7. Reduction of the double bond of 11-1 with hydrogen in thepresence of a catalyst such as PtO₂ or the like in a solvent such asacetic acid or the like provides cyclic amines of formula 11-2.Deprotection of 11-2 using procedures well known in the art (acidcatalyzed deprotection of BOC carbamate, e.g.) provides compounds offormula 11-3. Reaction of compounds of formula 11-3 with an appropriatealkylating agent such as ethylene carbonate in the presence of asuitable base such as sodium hydroxide provides compounds of the formula11-6. Compounds of formula 11-4 are also prepared by treatment ofcompounds of the formula 11-3 with an aldehyde such as formaldehyde andthe like and a reducing agent such as sodium triacetoxyborohydride orthe like in a solvent such as 1,2-dichloroethane or the like. Compoundsof formula 11-4 can also be prepared by the reaction of the amines offormula 11-3 with an acylating or sulfonating reagent, such as an acylanhydride, acyl chloride, sulfonyl chloride or the like, in the presenceof a suitable base such as pyridine, potassium carbonate, a tertiaryamine or the like, in appropriate solvents such as THF, dichloromethane,or others. Additionally amines of formula 11-3 can be treated withisocyanates or carbamates in appropriate solvents such as THF and thelike to provide ureas of the formula 11-4.

Reaction Scheme 12 outlines the preparation of compounds of 12-2 whereinR⁴ is described as 2-substituted morpholine attached by a methylenelinker and G³ is defined as above in Scheme 7. Ketone 12-1 (PG is eitherH or an optional protecting group well known to those in the art) canreduced directly under lewis acid mediated conditions (e.g. BF₃—OEt₂ andthe like) in the presence of a hydride source (e.g. triethylsilane andthe like). At this point the protecting group can be removed underconditions well known in the art (e.g. acid catalyzed removal of BOCcarbamates).

Additionally, sensitive or reactive groups on the compound of thisinvention may need to be protected and deprotected during any of theabove methods. Protecting groups in general may be added and removed byconventional methods well known in the art (see, for example, T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley:New York, (1999).

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their

Preparation of Intermediates Intermediate A: Preparation ofPyrrolo[2,1-f][1,2,4]triazin-4-ylamine

Step 1: Preparation of Pyrrol-1-yl-carbamic acid tert-butyl ester

A flask (fitted with a Dean-Stark trap) containing a stirred solution oftert-butylcarbazate (100, 0.757 mol), 2,5-dimethoxytetrahydrofuran (108g, 0.832 mol) and 2N HCl (10 mL) in 1,4-dioxane (700 mL) was heatedunder nitrogen at 90° C. As the reaction progressed over several hours,the solution changed from pale yellow to orange and began to reflux. Thereaction was monitored by the amount of distillate collected in the D/Strap (primarily CH₃OH, 2 moles/1 mole reagent). As methanol collectionapproached the theoretical amount (50 mL) a sample was analyzed by TLC(silica gel, GHLF, 1:3 EtOAc/hexane, ninhydrin stain) to confirmreaction completion. Heating was shut off and the reaction was allowedto cool somewhat before adding saturated sodium bicarbonate solution(˜25 mL) to neutralize the hydrochloric acid. The quenched mixture wasfiltered through a sintered-glass funnel and concentrated in vacuo toleave an orange, semi-solid residue. The residue was suspended indiethyl ether (minimum volume) and the nearly colorless solids werecollected by suction filtration, washed with hexane and air-dried toafford 60.2 g (40%) of product. A second crop (yellow-tan solids) fromthe mother liquors was isolated: 29.0 g, (19%). Additional materialwhich was present in the mother liquors could be recovered by silica gelchromatography to increase the yield.

¹H-NMR (CD₃OD): δ 10.23 (br s, 1H), 6.66 (t, 2H, J=2.2 Hz), 5.94 (t, 2H,J=2.2), 1.42 (s, 9H); MS: GC/MS (+esi): m/z=182.9 [MH]⁺

Step 2: Preparation of (2-Cyano-pyrrol-1-yl)-carbamic acid, tert-butylester

A 2L, 3-neck RB was fitted w/stir bar, N2 inlet, rubber septum low-temp.thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acidtert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolvedw/anhydrous acetonitrile (700 mL) and the stirred solution was cooled to0° C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwisevia syringe (maintaining an internal temp. below 5° C.); after ˜20minutes a suspension was observed. After 45 minutesN,N-dimethylformamide (anhydrous, 100 μL) was added dropwise viaaddition funnel (keeping internal temp. below 5° C.) and the reactionmixture became a solution. Stirring @0° C. was continued for 45 minutes,then the reaction was allowed to warm to RT; monitoring by TLC (silicagel, 1:3 ethyl acetate/hexane, UV, ninydrin stain) of a quenched sampleindicated that the reaction had progressed to completion. The mixturewas poured onto ice (˜2 L) and stirred with addition of EtOAc (2 L). Thelayers were separated and the organic layer was dried over magnesiumsulfate. The dried solution was filtered through a pad of 30/40 Magnesoland the filtrate was concentrated to dryness in vacuo, then the residuewas dissolved in a minimum volume of dichloromethane and chromatographedon a plug of silica gel, eluting with ethyl acetate/hexane, 0-50% ethylacetate. The clean, product-containing fractions were combined andconcentrated to dryness in vacuo, to afford the desired product as awhite solid, 69.8 g (62%). A somewhat impure fraction providedadditional material, 16.8 g (15%), bringing the total recovery to 86.6g, (77%). ¹H-NMR (CD₃OD): δ7.01 (dd, 1H, J=3.0, 1.6 Hz), 6.82 (dd, 1H,J=4.4, 1.7 Hz), 6.19 (dd, 1H, J=4.2, 2.9 Hz), 4.88 (s, 1H, H₂O+NH—),1.50 (br s, 9H, HN-BOC); MS: LC/MS (+esi), m/z=207.9 [M+H]

Step 3: Preparation of 1-Amino-1H-pyrrole-2-carbonitrile hydrochloride

A 3L, 3-neck RB flask was fitted with a mechanical stirrer, nitrogeninlet, thermocouple/JKEM thermocontroller, addition funnel and ice watercooling bath. (2-Cyano-pyrrol-1-yl)-carbamic acid, tert-butyl ester (85g, 0.41 mol) was added and dissolved with 1,4-dioxane (400 mL), then thestirred orange solution was cooled to 0° C. and HCl/dioxane (4N, 820 mL,8 eq.) was slowly added from the addition funnel, maintaining aninternal temperature below 5° C. After ˜30 minutes the solution becamecloudy and stirring@ room temperature was continued for 5 hours; thereaction was monitored for completion by TLC (silica gel, GHLF, 1:3EtOAc/hexane, UV; Note: the free base may be observed as a high-Rf spotand can be misinterpreted as incomplete reaction). The reaction mixturewas diluted with diethyl ether (2 L) and the precipitated solids werecollected by suction filtration and washed with ether (1 L). Drying(vacuum oven@50° C.) afforded the desired product as 50.5 g (85%) of atan solid. ¹H-NMR (CD₃OD): δ7.05 (dd, 1H, J=2.8, 1.9 Hz), 6.75 (dd, 1H,J=1.8, 4.2 Hz), 6.13 (dd, 1H, J=2.8, 4.4 Hz), 5.08 (s, 3H, NH₃ ⁺); MS:GC/MS, m/z=108.2 [M+H].

Step 4: Preparation of the Title Compound

To a stirred suspension of 1-Amino-1H-pyrrole-2-carbonitrilehydrochloride (50 g, 0.35 mol) in absolute ethanol (800 mL) was addedformamidine acetate (181.3 g, 1.74 mol) and potassium phosphate (370 g,1.74 mol). The suspension was heated for 18 hours@78° C. (under N₂),then cooled, filtered and concentrated to dryness in vacuo. The residuewas mixed with ice water (2 L) and the dark grayish-brown solids werecollected by suction filtration. The filter cake was washed with water,sucked dry and the solids were dissolved (on the funnel) with hot ethylacetate and filtered into a collection vessel. The dark solution wasfiltered through a long plug of 30/40 Magnesol and the pale yellowfiltrate was concentrated to dryness in vacuo to afford a yellow-tingedsolid (20.6 g, 44.1% yield). The plug was washed with ethylacetate/ethanol and the washings were concentrated in vacuo to affordadditional material, 10.7 g (23%). Extraction of the aqueous work-upfiltrate with ethyl acetate followed by drying, Magnesol filtration andconcentration gave another 6.3 g (14%) of clean product, bringing thetotal recovery to 37.6 g (81%). ¹H-NMR (CD₃OD): δ 7.72 (s, 1H), 7.52(dd, 1H, J=2.5, 1.6 Hz), 6.85 (dd, 1H, J=4.5, 1.6 Hz), 6.64 (dd, 1H,J=4.5, 2.7 Hz) LC/MS (+esi): m/z=135.1 [M+H].

Intermediate B: Preparation of7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine

A stirred solution containing pyrrolo[2,1-f][1,2,4]triazin-4-ylamine(21.0 g, 0.157 mol) in anhydrous DMF (200 mL) was cooled to −20° C. and1,3-dibromo-5,5-dimethylhydantoin (22.4 g, 0.078 mol) was addedportionwise over ˜45 minutes. The reaction was stirred for another 45minutes and monitored for completion by TLC (silica gel, GHLF, 5%CH₃OH/CH₂Cl₂). Saturated Na₂SO₃ solution (300 mL) was added, theresulting suspension was stirred and the solids were collected bysuction filtration. The filter cake was washed with water, dried bysuction and then partitioned between ethyl acetate (1L) and 5% sodiumcarbonate solution (1L). The layers were separated, the organic layerwas washed with fresh sodium carbonate solution and dried over magnesiumsulfate. The filtrate from the work-up was also extracted and combinedwith the main batch then filtered through a pad of Magnesol andconcentrated in vacuo to afford crude mono-bromide, KRAM 206-3-1, 29.9g, 90% yield. Trituration of a 21.5 g quantity of the crudemono-/di-bromo product in hot ethyl acetate (300 mL, 70° C.) providedcolorless solids (12.3 g) containing only ˜2% of the di-brominatedside-product. ¹H-NMR (CD₃OD): δ 7.84 (s, 1H), 6.95 (d, 1H, J=4.7 Hz),6.71 (d, 1H, J=4.7 Hz), 4.89 (s, 3H, —NH₂+H₂O); MS: LC/MS (+esi),m/z=213.1 [M+H].

Intermediate C:5-Bromo-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: 7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

A solution of formaldehyde (7.9 ml, 10.9 g, 134 mmol) and morpholine(8.0 ml, 11.7 g, 134 mmol) in AcOH (90 mL) was allowed to stir for 20minutes (slightly exothermic). A solution of the intermediate A (15.00g, 112 mmol) in AcOH (500 mL) was then added and the resulting mixturewas heated to 60° C. over night (Note-solution gets darker in color overtime). The reaction was concentrated in vacuo and the residue wasdissolved in EtOAc (˜300 mL) and washed with 1N NaOH (pH is ˜10) (˜300mL). The aqueous phase was back-extracted with EtOAc (3×100 mL). Becausethe product is somewhat water soluble and the aqueous extracts stillindicated heavy UV, the aqueous layer was diluted with brine (1:1) andextracted 3×100 mL EtOAc (note—pH of aqueous phase was checked aftereach extraction and re-adjusted with 1N NaOH to remain in the 9-10range). The combined organic layer was washed with brine (˜200 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to afford a yellowsolid. The crude material was recrystallized from 10% THF in EtOAc toafford 19.5 g (75% yield) of a light yellow free flowing solid. ProductR_(f)=0.20 in 9:1 DCM:EtOH ¹H-NMR (DMSO-d₆) δ 7.82 (s, 1H), 7.73 to 7.56(br s, 2H), 6.84 (d, J=4.5 Hz, 1H), 6.54 (d, J=4.4 Hz, 1H), 3.76 (s,2H), 3.52 (t, J=4.5 Hz, 4H), 2.38 (t, J=4.4 Hz, 4H); MS: LC/MS (+esi)RT=1.01 min m/z=234 [M+H]

Step 2. Preparation of Title Compound

In a 3-neck round bottom flask flushed with nitrogen was dissolved themorpholino pyrrolotriazine (8.91 g, 38.2 mmol) in THF (275 ml). Thisresulting solution was cooled to −78° C. (acetone/dry ice). To this wasadded the 1,3-Dibromo-5,5-dimethylhydantoin in 4 (approximately equal)portions (total amount used=5.242 g, 18.33 mmol, 0.48 equiv) 30 minutesapart. The reaction was allowed to stir for an additional 30 min at −78°C. and was then warmed to −45° C. with a dry ice/MeCN bath and stirredfor 30 min. Lastly, the reaction was allowed to warm to −10° C. in anice/acetone bath and allow to stir for an additional 30 min. TLC (9:1DCM:EtOH,) indicates major component is desired product (R_(f) 0.52)also note small amount of SM (R_(f)=0.20) and/or dibromide(R_(f)=0.58)-obtained through retro-mannich followed by bromination atC-7). The reaction was quenched at −10° C. with Sat'd Na₂SO₃ (30 mL) andstirred for 30 minutes, allowing reaction to warm to RT. The mixture wasdiluted with EtOAc (300 mL) and water (100 ml) and separated. Theaqueous phase was back-extracted with EtOAc (6×100 mL) (note-desiredproduct was highly water soluble). The combined organic layer was washedwith brine (200 mL), dried (Na₂SO₄), filtered and concentrated in vacuoto afford a light yellow solid. The crude material was recrystallizedfrom THF to afford 5.24 grams of slightly pink free flowing solid. Themother liquor was concentrated to provide a yellow residue and wasrecrystallized from THF to afford a second batch (1.73 grams, combinedyield of 58.5%) of slightly pink material. Product R_(f)=0.52 in 9:1DCM:EtOH. ¹H-NMR (DMSO-d₆) δ 7.86 (s, 1H), 6.72 (s, 1H), 3.75 (s, 2H),3.53 (t, J=4.5 Hz, 4H), 2.38 (t, J=4.3 Hz, 4H); MS: LC/MS (+esi),RT=0.25 min m/z=311.9 [M+H].

Intermediate D:4-[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]-piperazin-2-one

Step 1: Preparation of4-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazin-2-one

A solution of paraformaldehyde (726 mg, 8.95 mmol) and 2-oxopiperazine(1.49 g, 14.9 mmol) in acetic acid (35 ml) was stirred under nitrogenfor 10 minutes and then Intermediate A (1.00 g, 7.46 mmol) was added.The resultant mixture was heated at 60° C. for 2 hr and then evaporatedin vacuo to give dark oily residue. This raw product was diluted withabout 200 ml of EtOAc and then filtered twice to remove a very darksolid which was rinsed with additional EtOAc and give an orange filtratewhich was mixed with saturated aqueous NaHCO3 to precipitate a creamcolored solid precipitate. This material was collected by filtration,washed with water and EtOAc and then dried in vacuo to give pure4-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazin-2-one (948mg, 52%).

¹H-NMR (DMSO-d₆) δ 7.82 (s, 1H), 7.6-7.7 (bs, 3H), 6.86 (d, 1H, J=4.8),6.56 (d, 1H, J=4.8), 3.85 (s, 2H), 3.09 (m, 2H), 2.91 (s, 2H), and 2.55(m, 2H); MS LC-MS [M+H⁺=247.3 and [M+Na]⁺=275.9, RT=1.03 min.

Step 2: Preparation of the Title Compound

A suspension of4-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazin-2-one (900mg, 3.65 mmol) was stirred under nitrogen in DMF (24 ml) astrifluoroacetic acid (0.40 ml, 5.2 mmol) was added via syringe resultingin a solution. This solution was stirred under nitrogen with −20 to −30°C. bath cooling as 1,3-dibromo-5,5-dimethylhydantoin (470 mg, 01.65mmol) was added in 6 portions every 5-20 minutes. A small aliquot wasremoved, diluted with MeOH and assayed by HPLC to show that 87 area %product had formed along with about 2% later side product thought to bedibromide. The reaction mixture was diluted with EtOAc and washed withca 20 ml saturated NaHCO₃. The aqueous was back extracted three timeswith 10% isopropanol in dichloromethane. The combined extract was dried(Na₂SO₄) and evaporated in vacuo. The residue was chromatographed on 40g silica gel using a gradient from 0-10% MeOH in CH₂Cl₂. The bestfractions were combined, evaporated and the residue was triturated witha mixture of hot THF, MeOH and CH₂Cl₂ and then cooled in a refrigeratorbefore collecting the solid which was dried in vacuo to give pure4-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazin-2-one (724mg, 61%).

¹H-NMR (DMSO-d₆) δ 7.86 (s, 1H), 7.71 (bs, 1H), 6.76 (s, 1H), 3.84 (s,2H), 3.09 (m, 2H), 2.93 (s, 2H), and 2.56 (t, 2H, J=5.4); MS LC-MS[M+H]⁺=325/327 (weak), RT=1.08 min.

Intermediate E: Preparation of5-(4-aminophenyl)-7-(morpholin-4ylmethyl)pyrrolo-[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde

To a solution of Intermediate B (50 mg, 0.23 mmol) in THF (2 ml) at −78°C. under N₂ was added n-butyllithium (0.38 ml, 0.93 mmol) slowly. Afterstirred for 15 min, DMF (0.10 ml, 1.4 mmol) was added and the dry-icebath was removed and the reaction was allowed to warm up to rt. Thereaction mixture was diluted with ethyl acetate and was quenched withH₂O. The organic was collected, dried over Na₂SO₄ and concentrated toyield 34 mg of a mixture of the title compound and a byproductpyrrolo[2,1-f][1,2,4]triazin-4-amine. The mixture was not separable viacolumn chromatography and was subject to next step reaction withoutfurther purification. ¹H-NMR (DMSO-d₆) δ 10.3 (—CHO). MS [M+H]⁺=163.2;LCMS RT=1.11 min.

Step 2: Preparation of7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde(235 mg, 1.45mmol) in 1,2-dichroloethane (5 ml) was added morpholine (0.25 ml, 2.9mmol) and sodium triacetoxyborohydride (611 mg, 2.9 mmol). The reactionmixture was stirred at rt under N₂ for 16 h. The reaction was quenchedwith saturated aq. sodium bicarbonate and followed by extraction withCH₂Cl₂. The organic was dried over Na₂SO₄, concentrated and purified viacolumn chromatography (5:95 v/v CH₃OH—CH₂Cl₂) to afford 66 mg of thetitle compound (yield 20%). ¹H-NMR (DMSO-d₆) δ 7.80 (s, 1H), 7.62 (br,2H), 6.83 (d, J=4 Hz, 1H), 6.52 (d, J=4 Hz, 1H), 3.75 (s, 2H), 3.51(t,J=4 Hz, 4H), 2.37(t, J=4 Hz, 4H); MS [M+H]⁺=234; LCMS RT=1.00 min.

Step 3: Preparation of5-bromo-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (562 mg,2.40 mmol) in THF (19 ml) at −20 C was added1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (344 mg, 1.2 mmol) inthree portions. The reaction was stirred at −20 C for 3 h. Upon thecompletion, the reaction was quenched with aqueous saturated Na₂SO₃ andallowed to warm up to rt. The crude was extracted with ethyl acetate.The organic was washed with brine, dried over Na₂SO₄ and concentrated.The resulting crude was purified via column chromatography (95:5 v/vCH₂Cl₂—CH₃OH) to afford 600 mg of the title compound as yellow solid(yield 79%). ¹H-NMR (DMSO-d₆) δ 7.84 (s, 1H), 6.71 (s, 1H), 3.74 (s,2H), 3.51 (t, J=4 Hz, 4H), 2.37(t, J=4 Hz, 4H); MS [M+H]⁺=312; LCMSRT=1.04 min.

Step 4. Preparation of Title Compound

A mixture of Intermediate C (100 mg, 0.32 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (210 mg, 0.96mmol), 2M Na₂CO₃(0.48 ml, 0.96 mmol) andtetrakis(triphenylphosphine)palladium (37 mg, 0.03 mmol) in1,2-dimethoxyethane (2 ml) was degassed and filled with N₂ and was sheated at 80 C under N₂ for 16 h. After cooled to rt, the reactionmixture was partitioned between CH₂Cl₂ and water. The aqueous phase wasextracted with CH₂Cl₂ two times. The combined organic was washed withbrine and dried over Na₂SO₄. The crude was concentrated to give the rawproduct as yellow oil. The resulting crude oil was purified via columnchromatography (95:5 v/v CH₂Cl₂—CH₃OH) to afford 52 mg of the titlecompound (yield 50%). ¹H-NMR (DMSQ-d₆) δ 7.83 (s, 1H), 7.10(d, J=9 Hz,2H), 6.63(d, J=9 Hz, 2H), 6.49(s, 1H), 5.24(s, 2H), 3.78 (s, 2H), 3.51(t, J=4 Hz, 4H), 2.41(t, J=4 Hz, 4H); MS [M+H]⁺=324.9; LCMS RT=1.00 min.

Intermediate F:5-(4-amino-3-fluorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f]-[1,2,4]triazin-4-amine

Step 1: Preparation of tert-butyl{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}carbamate

To a solution of Intermediate C (500 mg, 1.6 mmol) in dioxane (30 mL)and 2N Na2CO3 (30 mL) was added Intermediate P (576 mg, 1.68 mmol). Thesolution was degassed and back filled with N₂. Palladium tetrakistriphenylphosphine (185 mg, 0.16 mmol) was added and the reactionmixture was heated to 80° C. over night. The reaction was cooled to roomtemperature and diluted with EtOAc (100 mL). The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theproduct was purified by flash column chromatography (Eluent gradient1-10% MeOH/CH₂Cl₂) to provide the t-butyl{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-][1,2,4]triazin-5-yl]-2-fluoro-phenyl}carbamate(1.9 g, 4.29 mmol) as a white powder in 92% yield. ¹H-NMR (DMSO-d₆)δ9.08 (s, 1H), 7.90 (s, 1H), 7.70 (t, J=8.4 Hz, 1H), 7.27 (dd, J=12, 2Hz, 1H), 7.20 (dd, J=8.4, 2 Hz, 1H), 6.65 (s, 1H), 3.80 (s, 2H), 3.54(m, 4H), 2.43 (m, 4H), 1.46 (s, 9H); MS [M+H]⁺=442.8; LCMS RT=2.18.

Step 2. Preparation of Title Compound

To a slurry of the t-butyl carbamate (510 mg, 1.15 mmol) in CH₂Cl₂ (10mL) was added TFA (5 mL). The reaction mixture became homogenousinstantly and was allowed to stir for 1 h. The reaction mixture waspoured into 1N aqueous NaOH (100 mL) and extracted with EtOAc (100 mL).The organic layer was dried over Na₂SO₄ and concentrated in vacuo toprovide the title compound (392 mg, 1.14 mmol) in 99% yield. The productwas used immediately without further purification. ¹H-NMR ([DMSO-d₆)δ7.86 (s, 1H), 7.07 (dd, J=12, 2 Hz, 1H), 6.95 (dd, J=8, 2 Hz, 1H), 6.82(dd, J=9.4, 8 Hz, 1H), 6.55 (s, 1H), 5.29 (s, 2H), 3.79 (s, 2H), 3.54(m, 4H), 2.43 (m, 4H).

Intermediate G:5-(4-amino-3-fluorophenyl)-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate F was used toprepare the title compound by substituting thiomorpholine 1,1-dioxidefor morpholine.

Intermediate H: Preparation of phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate

A solution of the commerically available2-amino-4-trifluoromethylpyridine (20.86 g, 128.7 mmol) in 250 mL CH₂Cl₂was treated with phenylchloroformate (17.81 mL, 141.5 mmol) and pyridine(22.85 mL, 283 mmol). During addition of the pyridine a yellowprecipitate formed and a considerable exotherm was observed. After 0.5 hthe homogeneous reaction was diluted with 1 L Et₂O and washed with 1Nbisulfate buffer (pH 2) and sat. NaHCO₃. The organic layer was driedwith Na₂SO₄ and evaporated to yield a gray solid. Tritruration withEt₂O:hexanes (1:5) gave the title compound as cottony white crystals(33.5 g, 92% Yield). ¹H-NMR (DMSO-d₆) δ 11.28 (s, 1H), 8.60 (d, J=5.1Hz, 1H), 8.12 (bs, 1H), 7.40 to 7.48 (m, 3H), 7.22 to 7.31 (m, 3H); MS[M+H]⁺=283.1; LCMS RT=3.51.

Intermediate I: Preparation of tert-butyl4-{[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazine-1-carboxylate

Step 1: Preparation of tert-butyl4-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate

The procedure used for the preparation of Intermediate C, Step 1 wasused to prepare the t-butyl4-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylateby substituting tert-butyl piperazine-1-carboxylate for morpholine.¹H-NMR (DMSO-d₆) δ 7.81(s, 1H), 7.63(br, 2H), 6.83(d, J=4 Hz 1H),6.53(d, J=5 Hz, 1H), 5.74(s, 1H), 3.99 (s, 2H), 3.39 to 3.34(m, 4H),2.35 to 2.30(m, 4H), 1.97(s, 3H); MS [M+H]⁺=330.0; LCMS RT=1.16 min.

Step 2:4-(4-amino-5bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-piperazine-1-carboxylicacid tert-butyl ester

To a solution of4-(4amino-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-piperazine-1-carboxylicacid tert-butyl ester (252 mg, 0.758 mmol) in THF (8 mL) at −20° C. (IPAand dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione(108 mg, 0.379 mmol). The reaction was stirred at −20° C. for 4 h. Afterremoval of solvent, the residue was purified by silica gel column using4% methanol in dichloromethane to obtain 209 mg (67%) of desiredproduct. ¹H-NMR (CD₂Cl₂) δ 7.81 (s, 1H), 7.23 (s, 1H), 6.61 (s, 1H),3.86 (s, 1H), 3.41 (t, J=2.4, 4H), 2.48 (s, 4H), 1.43 (s, 9H) MS[M+H]⁺=410.9; LCMS RT=1.87 min

Step 3: Preparation of Title Compound

The procedure used for the preparation of Intermediate E, step 4 wasused to prepare the t-butyl4-{[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methyl}piperazine-1-carboxylateby substituting4-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-piperazine-1-carboxylicacid tert-butyl ester for Intermediate C.

Intermediate J: Preparation of7-[(4-acetylpiperazin-1-yl)methyl]-5-(4-amino-3-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of7-[(4-acetylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate C, Step 1 wasused to prepare7-[(4-acetylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-amineby substituting N-acetyl piperizine for morpholine. ¹H-NMR (DMSO-d₆) δ7.81(s, 1H), 7.63(br, 2H), 6.83(d, J=4 Hz 1H), 6.53(d, J=5 Hz, 1H),5.74(s, 1H), 3.99 (s, 2H), 3.39 to 3.34(m, 4H), 2.35 to 2.30(m, 4H),1.97(s, 3H) ; MS [M+H]⁺=275.1; LCMS RT=1.02 min.

Step 2 Preparation of7-[(4-acetylpiperazin-1-yl)methyl]-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate C, step 2 wasused to prepare7-[(4-acetylpiperazin-1-yl)methyl]-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amineby substituting7-[(4-acetylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-4-aminefor 7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. ¹H-NMR(DMSO-d₆) δ 7.82(s, 1H), 6.72(s, 1H), 3.81(s, 2H), 3.42 to 3.38(m, 4H),2.45 to 2.40(m, 4H), 1.95(s, 3H); MS [M+H]⁺=354.9; LCMS RT=1.10 min.

Step 3: Preparation oftert-butyl(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-amino-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)carbamate

The procedure used for the preparation of Intermediate F, step 1 wasused to prepare the t-butyl(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-amino-pyrrolo[2,1-f][1,2,4]triazin-5yl}-2-fluorophenyl)carbamateby substituting7-[(4-acetylpiperazin-1-yl)methyl]-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-aminefor Intermediate C. MS [M+H]⁺=483.9; LCMS RT=2.15 min.

Step 4: Preparation of Title Compound

To a solution of t-butyl(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)carbamate(320 mg, 0.62 mmol) in CH₂Cl₂ (8 ml) was added TFA (3 ml) and wasstirred at rt for 3 h. The reaction mixture was partially evaporated andwas added 10 ml ethyl acetate and washed with saturated aq. NaHCO₃. Theorganic was dried over Na₂SO₄, concentrated and purified via columnchromatography (95:5, v/v, CH₂Cl₂—CH₃OH) to afford 74 mg of the titlecompound (yield 30%). ¹H-NMR (CH₃OH-d₄) δ 7.85 (s, 1H), 7.10 to 7.00 (m,3H), 6.66 (s, 1H), 4.00(s, 2H), 3.60 to 3.50(m, 4H), 2.63 to 2.55(m,4H), 20.6(s, 3H); MS [M+H^(]+)=383.9; LCMS RT=1.10 min.

Intermediate K: Preparation of5-(4-amino-3-methoxyphenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of tert-butyl{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2methoxyphenyl}carbamate

The procedure used for the preparation of IntermediateF, step 1 was usedto prepare the t-butyl{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2methoxyphenyl}carbamateby substituting Intermediate BV for Intermediate X (t-butyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboraolan-2-yl)phenyl]carbamate)and substituting 1,4-dioxane for 1,2-dimethoxyethane. ¹H-NMR (DMSO-d₆) δ7.98(s, 1H), 7.89 (s, 1H), 7.78 (d, J=8 Hz, 1H), 7.05(d, J=2 Hz, 1H),6.96 (dd, J=8, 2 Hz, 1H), 6.65 (s, 1H), 3.83 (s, 3H), 3.80(s, 2H), 3.53(t, J=4 Hz, 4H), 2.42(t, J=4 Hz, 4H), 1.41(s, 9H); MS [M+H]⁺=455.0; LCMSRT=2.44 min.

Step 2: Preparation of Title Compound

To a solution of t-butyl{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2methoxyphenyl}carbamate(100 mg, 0.22 mmol) in CH₂Cl₂ (4 ml) was added trifluoroacetic acid (1.5ml) and was stirred at rt for 3 h. The reaction mixture was partiallyevaporated and was added 10 ml ethyl acetate and washed with saturatedaq. NaHCO₃. The organic was dried over Na₂SO₄ and concentrated to afford80 mg of the title compound. ¹H-NMR (DMSO-d₆) δ 7.84 (s, 1H), 6.84 (d,J=2 Hz, 1H), 6.84 to 6.68 (m, 2H), 6.55 (s, 1H), 4.87 (s, 2H), 4.01 to3.99(m, 5H), 3.53 (t, J=4 Hz, 4H), 2.42(t, J=4 Hz, 4H).

Intermediate L Preparation of5-(4-amino-2-methylphenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate E, Step 4 wasused to prepare the title compound by substituting Intermediate BU for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and toluene for1,2-dimethoxyethane. ¹H-NMR (DMSO-d₆) δ 7.82 (s, 1H), 6.86(d, J=8 Hz,2H), 6.50(d, J=2 Hz, 1H), 6.42(d, J=8 Hz, 2H), 5.16(s, 2H), 3.78 (s,2H), 3.53 (t, J=4 Hz, 4H), 2.41(t, J=4 Hz, 4H), 1.97(s, 3H); MS[M+H]⁺=338.9; LCMS RT=1.01 min.

Intermediate M: Preparation ofN-[2-fluoro-5-(trifluoro-methyl)phenyl]-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

To a solution of 1,2 dichloroethane (80 mL) was added4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.00 g, 22.82mmol) and allowed to stir until completely dissolved. To this solutionwas added 2-fluoro-5-trifluoromethyl phenylisocyante (4.92 g, 23.96mmol) in one portion. The solution was allowed to stir overnight at rt,and then filter off the solids obtained. Rinse with 1,2 dichloroethane.A second crop of product is obtained by concentrating the mother liquor,stirring in 20 ml of 1,2 dichloroethane, filtering, and rinsing with 1,2dichloroethane. Total amount of white crystals obtained was 9.56 g(22.54 mmol, 98.8% yield). ¹H-NMR (DMSO-d₆) δ 9.30 (s, 1H), 8.92 (s,1H), 8.60 (d, J=5.0 Hz 1H), 7.60 (d, J=6.8 Hz, 2H), 7.51 to 7.46 (m,3H), 7.4 to 7.36 (br m, 1H), 1.26 (s, 12H); MS [M+H]⁺=425 LCMS RT=4.11min.

Intermediate N: Preparation ofN-[2-chloro-5-(trifluoro-methyl)phenyl]-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea

The procedure used for the preparation of Intermediate M was used toprepare the title compound by substituting 2chloro-5-trifluoromethylphenylisocyante for 2-fluoro-5-trifluoromethyl phenylisocyante. ¹H-NMR(DMSO-d₆) δ 9.71 (s, 1H), 8.63 (m, 2H), 7.71 (d, J=8.2 Hz, 1H), 7.61 (d,J=6.8 Hz, 2H), 7.49 (d, J=6.9 Hz, 2H), 7.37 (d, J=8.0 Hz 1H), 1.26 (s,12H); MS [M+H]⁺=441 LCMS RT=4.38 min

Intermediate O: Preparation ofN-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1. Preparation ofN-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of 1,2 dichloroethane (100 mL) was added4-Bromo-2-fluoroaniline (5.00 g, 26.31 mmol) and allowed to stir untilcompletely dissolved. To this solution was added2-fluoro-5-trifluoromethyl phenylisocyante (5.67 g, 27.63 mmol) in oneportion. The solution was allowed to stir overnight at rt, and thenfilter off the solids obtained. Rinse several times with 1,2dichloroethane (15 ml total). A second crop of product was obtained byconcentrating the mother liquor, stirring in 20 ml of 1,2dichloroethane, heat to reflux with stirring, cool to rt, filter, andrinse with 1,2 dichloroethane. Total amount of white solids obtained was10.13 g (25.64 mmol, 97.4% yield). ¹H-NMR (DMSO-d₆) δ 9.37 (s, 1H), 9.23(s, 1H), 8.60 (d, J=7.2 Hz 1H), 8.15 (t, J=8.8 Hz, 1H), 7.58 to 7.50(dd, J=8.9, 2.2 1H), 7.48 (m, 1H), 7.40 to 7.32 (m, 2H); LCMS RT=4.22min.

Step 2: Preparation of Title Compound

To a solution of 1,4-dioxane (60 mL) was added theN-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea(10.00 g, 25.31 mmol, intermediate B) and allowed to stir undernitrogen. DMF is added dropwise until solution was homogeneous. Reactionwas degassed 3×. To this solution was added Bis(pinacolato)diboron (7.71g, 30.37 mmol) in one portion. Reaction was degassed 5×. Potassiumacetate (7.45 g, 75.92 mmol) was then added in one portion. Reaction wasthen degassed 3× more. To this heterogeneous reaction was added1,1′-Bis(diphenylphosphino)ferrocenepalladium dichloride (925 mg, 1.26mmol). Reaction was degassed 5× and then heated to 80° C. and allowed tostir at temperature overnight. Reaction is filtered through a thin padof silica to remove solids and then purified via flash column using agradient of 15:1 to 5:1 Hex:EtOAc to obtain 12.24 g as a white solid.(109% yield, 27.68 mmol used as is). ¹H-NMR (DMSO-d₆) δ 9.46 (s, 1H),9.33 (s, 1H), 8.63 (d, J=7.4 Hz 1H), 8.28 (t, J=8.2 Hz, 1H), 7.52 to7.35 (br m, 4H), 1.27 (s, 12H); MS [M+H]⁺=443; LCMS RT=4.31 min.

Intermediate P: Preparation oftert-butyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

Step1: Preparation of tert-butyl(4-bromo-2-fluorophenyl)carbamate

To a solution of THF (400 ml) in a water bath was added4-bromo-2-fluoroaniline (50 g, 263.13 mmol). To this solution is added a1M solution of sodium bis(Trimethylsilyl)amide in THF (526 ml) dropwiseover 1 hour. Di-tert-butyl dicarbonate is dissolved in 100 ml of THF andadded dropwise to the reaction flask. Stir at RT for 2 hours. Reactionsolution is now poured into 1.2 L of saturated sodium bicarbonate andstirred. Add 1.2 L of diethyl ether and extract. Extract 2× more withdiethyl ether (500 ml each) and combine organics. Wash organics 2×water, 1× brine, separate, dry organics over sodium sulfate, filter andstrip of solvent to obtain 65.6 g (85.9%, 226.10 mmol) orange waxysolids that are used as is. ¹-NMR (DMSO-d₆) δ 9.08(s, 1H), 7.58 (t,J=8.5 Hz 1H), 7.49 (dd, J=10.4, 2.4 Hz 2H), 7.32 to 7.29 (m, 1H), 1.45(s, 12H); LC RT=3.77 min

Step 2: Preparation of Title Compound

The procedure used for the preparation of Intermediate O, step 2 wasused to prepare the title compound by substituting tert-butyl(4-bromo-2-fluorophenyl)carbamate (41 g, 141.31 mmol) forN-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.

¹H-NMR (DMSO-d₆) δ 9.16(s, 1H), 7.76 (t, J=8.0 Hz 1H), 7.41 (d, J=8.1 Hz1H), 7.31 (d, J=11.3 Hz 1H), 1.45 (s, 9H), 1.27 (s, 12H); LC RT=4.25 min

Intermediate Q: Preparation ofN-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-(4-bromo-2-fluorophenyl)-N′-[3-(trifluoromethyl)-phenyl]-urea

To a solution of 4-bromo-2-fluoroaniline (3.0 g, 15.8 mmol) in THF (15mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (3.55 g, 18.9mmol). The reaction was stirred at room temperature overnight. Solidproduct was present in the reaction vessel. Product was furtherprecipitated by the addition of 1:2 ether/hexanes. The solids werecollected by filtration, dried under hi vacuum and found to be cleantitle compound in 60% yield. ¹H-NMR (DMSO-d₆) δ 9.44 (s, 1H), 8.76 (d,J=1.2 Hz, 1H), 8.12 (t, J=8.7, 1H), 8.05 (s, 1H), 7.64-7.37 (m, 5H); MS[M+H]⁺=378.9, LCMS RT=3.92 min.

Step 2: Preparation of Title Compound

Potassium acetate (1.56 g, 15.9 mmoL) and the bis(pinacolato)diboron(1.35 g, 5.3 mmol) were added as solids to a flask then placed under N2.N-(4-bromo-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea (2.0 g,5.3 mmol) in DMSO (30 mL) was then added to the flask. The reaction wastaken through three purge-fill cycles using high vacuum then nitrogen.Pd(dppf)₂Cl₂CH₂Cl₂ (0.129 g, 0.159 mmol) was added. The reaction wasagain placed under vacuum then blanketed with nitrogen. The reaction washeated at 80° C. until TLC showed the complete consumption of startingbromide (approximately 90 minutes). The reaction was cooled to roomtemperature. ETOAc was added, the reaction was then partitioned betweenEtOAc and saturated aqueous bicarbonate. The organic layer was washedwith brine seven times to remove DMSO. The material was then dried withNa₂SO₄ and concentrated under vacuum. The residue was chromatographedwith eluent 0-30% v/v ETOAc/Hexanes. Pure product was thus obtained in73% yield. ¹H-NMR (DMSO-d₆) δ 9.52 (s, 1H), 8.85 (s, 1H) 8.27 (t, J=8.1Hz, 1H), 8.07 (s, 1H), 7.56-7.37 (m, 5H), 1.31 (s, 12H); MS[M+H]⁺=425.3, LCMS RT=4.24 min.

Intermediate R: Preparation ofN-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[2fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Potassium acetate (3.54 g, 36.1 mmol) and the boronate (3.36 g, 13.2mmol) were added as solids to a flask then placed under N2.4-bromo-2,6-difluoroaniline (2.50 g, 12.0 mmol) in DMSO (30 mL) was thenadded to the flask. The reaction was taken through three purge-fillcycles using high vacuum then nitrogen. Pd(dppf)CH₂Cl₂ (0.129 g, 0.159mmol) was added. The reaction was again placed under vacuum thenblanketed with nitrogen. The reaction was heated at 80° C. until TLCshowed the complete consumption of starting bromide (approximately 90minutes). The reaction was cooled to room temperature. ETOAc was added,the reaction was then partitioned between EtOAc and saturated aqueousbicarbonate. The organic layer was washed with brine seven times toremove DMSO. The material was then dried with Na₂SO₄ and concentratedunder vacuum. The residue was chromatographed with eluent 0-100% v/vCH₂Cl₂/Hexanes. Pure product was obtained in 62% yield. ¹H-NMR (DMSO-d₆)δ 7.03 (dd, J=6.6 Hz, 1.8 Hz, 2H), 5.76 (s, 2H) 1.26 (s, 12H); MS[M+H]⁺=256.3, LCMS RT=3.30 min; R_(f)=0.37 in 40% CH₂Cl₂/Hexanes.

Step 2: Preparation of the Title Compound

To a solution of2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.300 g, 1.18 mmol) in THF (2 mL) was added1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.314 g, 1.53 mmol).The reaction was stirred at 45 C overnight. Solid product was present inthe reaction vessel. Product was further precipitated by the addition of1:3 ether/hexanes. The solids were collected by filtration, dried underhi vacuum and found to be clean title compound in 71% yield. ¹H-NMR(DMSO-d₆) δ 7.03 (dd, J=6.6, 1.8 Hz, 2H), 5.76 (s, 2H), 1.26 (s, 12H);MS [M+H]⁺=461.2, LCMS RT=4.11 min.

Intermediate S: Preparation ofN-[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation ofN-(4-bromo-2,6-difluorophenyl)-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

4-bromo-2,6-difluoroaniline (0.300 g, 1.44 mmol) was weighed into avial, THF (3 mL) was added. Intermediate H (407 mg, 1.44 mmol) was addedas a solid, followed by TEA (0.437 g, 4.37 mmol). The vial was cappedand the reaction was heated at 60° C. overnight. Product wasprecipitated by the addition of hexanes. The solids were rinsed with 2:1hexanes/ether to yield clean product (66%). ¹H-NMR (DMSO-d₆) δ 10.0 (s,1H), 9.27 (s,1H), 8.51 (d, J=5.4 Hz, 1H), 7.91 (s, 1H), 7.55 (m, 2H)7.37 (m, 1H), MS [M+R]⁺=396.0, LCMS RT=3.62 min.

Step 2: Preparation of the Title Compound

The title compound was prepared using step 2 of the procedure to makeIntermediate Q by substitutingN-(4-bromo-2,6-difluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]ureafor the bromide. Material was used crude thus no isolated yield wasrecorded. ¹H-NMR (DMSO-d₆) δ 9.99 ((s, 1H), 9.39 (s, 1H), 8.54 (m,1H),7.94 (s,1H), 7.44-7.11 (m, 3H), 1.29 (s, 12H); MS [M+H]⁺=444.1, LCMSRT=4.01 min.

Intermediate T: Preparation ofN-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)amine

2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline wasprepared following step 1 of the procedure to make Intermediate S bysubstituting 4Bromo 2, 5 difluoroaniline for the bromide. ¹H-NMR(DMSO-d₆) δ 7.03 (dd, J=11.7 Hz, 5.4 Hz, 1H), 6.38 (dd,10.8 Hz, 3.9 Hz,1H), 5.91 (s 2H) 1.22 (s, 12H); MS [M+H]⁺=256.3, LCMS RT=3.13 min.

Step 2: Preparation of the Title Compound

N-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[4-(trifluoro-methyl)pyridin-2-yl]ureawas prepared using step 1 of the procedure to make Intermediate S byreplacing the aniline with2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.¹H-NMR (DMSO-d₆) δ; 10.25 (s, 1H), 8.55 (m, 1H), 8.15-7.97 (m, 2H)7.47-7.23 (m, 3H), 1.27 (s, 12H); MS [M+H]⁺=444.1, LCMS RT=4.01 min.

Intermediate U: Preparation ofN-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline wasprepared following step 1 of the procedure to make Intermediate R bysubstituting 4-Bromo 3 fluoroaniline for the bromide. ¹-H-NMR (DMSO-d₆)δ 7.24 (t, J=4.8 1H), 6.31 (dd, J=8.1, 2.1 Hz, 1H), 6.16 (dd, J=12.3 Hz,2.4 Hz, 1H) 5.81 (s, 2H), 1.22 (s, 12H); MS [M+H]⁺=238.4, LCMS RT=3.07min.

Step 2: Preparation of Title Compound

N-[3-fluoro-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[4-(trifluoro-methyl)pyridin-2-yl]ureawas prepared using step 1 of the procedure to make Intermediate S byreplacing the aniline with3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

¹H-NMR (DMSO-d₆) δ;10.0 (s, 1H) 9.80 (s,1H), 8.54 (d, J=5.4 Hz, 1H),8.02 (s, 1H), 7.56-7.18 (m, 4H), 1.27 (s,12H); MS [M+H]⁺=426.1, LCMSRT=4.04 min.

Intermediate V: Preparation of5-bromo-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of3-(4-Aminopyrrolo[2,1-f][1,2,4]trazin-7-yl)-prop-2-yn-1-ol

To a degassed solution of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-ylamine(10.0 g, 46.9 mmol) in anhydrous DMF (78 mL) and triethylamine (47 mL)was added tetrakis(triphenylphosphine)palladium(0) (2.17 g, 1.88 mmol,0.04 eq) and copper (I) bromide dimethylsulfide complex (0.77 g, 3.75mmol, 0.08 eq). After degassing with N₂ for 5 min., propargyl alcohol(8.2 mL, 140.8 mmol, 3.0 eq) was added, and the reaction mixture wasstirred at 90° C. for 6 h. The reaction was quenched with 5% aq. NH₃ insaturated aq. NH₄Cl. The aqeuous layer was washed with EtOAc (1×)followed by 25% iPrOH in DCM (3×). The combined organic layers weredried over MgSO₄, filtered through a pad of celite, and concentrated atreduced pressure. The crude product was purified by MPLC eluted with 5%EtOH/DCM. Trituration from EtOAc afforded 4.75 g (53.8%) of the desiredproduct as a yellow solid. ¹H-NMR (DMSO-d₆) δ7.89 (s, 1H), 7.88 (broads, 2H), 6.85 (dd, 2H), 5.39 (t, 1H), 4.36 (d, 2H); MS LC-MS [M+H]⁺=189,RT=1.08 min.

Step 2: Preparation of3-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol

Palladium on carbon (474 mg, 10% by wt.) was placed under an inertatmosphere and suspended in EtOH (15 mL). A solution of3-(4-aminopyrrolo[2,1-f][1,2,4]trazin-7-yl)-prop-2-yn-1-ol (4.74 g, 25.2mmol) dissolved in 2:1 v/v EtOH/THF was added. The reaction mixture wasplaced under H₂ atmosphere (1 Atm pressure) and stirred overnight. Theresulting mixture was filtered through a pad of Celite® and the solventwas concentrated under reduced pressure. Trituration from EtOAc/hexaneafforded 4.64 g (95.8%) of the desired product as an off-white solid.¹H-NMR (DMSO-d₆) δ 7.77 (s, 1H), 7.54 (broad s, 2H), 6.78 (d, 1H), 6.39(d, 1H), 4.50 (t, 1H), 3.43 (q, 2H), 2.84 (t, 2H), 1.74 to 1.82 (m, 2H);MS LC-MS [M+H]⁺=193, RT=1.06 min.

Step 3: Preparation of3-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol

To a solution of3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (5.40 g, 28.09mmol) in anhydrous DMF (56 mL) was added1,3-dibromo-5,5-dimethylhydantoin (3.96 g, 13.9 mmol, 0.50 eq)proportionwise at −50° C. The reaction mixture was warmed to 0° C. andstirred at 0° C. for 2 h. The reaction mixture was quenched with waterand poured into EtOAc. The organic layer was washed with water andbrine, dried over Na₂SO₄, filtered, and concentrated at reducedpressure. Crystallization from DCM afforded 6.54 g (85.9%) of thedesired product as a beige solid. ¹H-NMR (DMSO-d₆) δ 7.83 (s, 1H), 6.61(s, 1H), 4.52 (broad s, 1H), 3.41 (t, 2H), 2.83 (t, 2H), 1.75 to 1.77(m, 2H); MS LC-MS [M+H]⁺=271/273, RT=1.40 min.

Step 4: Preparation of5-bromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of3-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (1.20g, 4.43 mmol) in anhydrous THF (22 mL) at 0° C. was added carbontetrabromide (1.62 g, 4.87 mmol, 1.1 eq) and triphenylphosphine (1.16 g,4.43 mmol, 1.0 eq). After 5 minutes the ice bath was removed and thereaction mixture was stirred at RT for 1 hour. Then another 0.1equivalents of both carbon tetrabromide (0.15 g, 0.44 mmol) andtriphenylphosphine (0.12 g, 0.44 mmol) were added. The reaction wasstirred another hour at ambient temperature before it was filtered toremove some solid which was rinsed with some THF. The combined filtrateand rinse were concentrated at reduced pressure to give a crude productwhich was purified by MPLC on 120 g of silica gel eluted with a gradientfrom 0-100% EtOAc in hexane to give 950 mg (64.2%) of desired product asa white solid after evaporation of best fractions which eluted from55-65% EtOAc. ¹H-NMR (DMSO-d₆) δ 7.84 (s, 1H), 6.65 (s, 1H), 3.54 (t,2H, J=6.4), 2.94 (t, 2H, J=6.4), and 2.16 (q, 2H, J=6.4); MS LC-MS[M+H]⁺=333.3/335.1/337.1, RT=2.77 min. Evidence showed in the NMR andthe LC-MS for about 16% contamination with5,6-dibromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine whichcame from an analogous contaminant(3-(4-Amino-5,6-dibromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol)in the starting material. Products that came from this contaminant wereremoved by chromatography of the product of step 5 below.

Step 5: Preparation of the Title Compound

A solution of5-bromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (931 mg,2.78 mmol), morpholine (1.214 g, 13.94 mmol, 5.0 eq), triethylamine(1.16 ml, 8.36 mmol, 3.0 eq), and sodium iodide (63 mg, 0.42 mmol, 0.15eq) in anhydrous DMF (20 mL) was stirred at 55° C. for 17 h. Thereaction mixture was diluted with EtOAc and washed with saturatedaqueous NaHCO₃ followed by saturated brine. It was dried over Na₂SO₄,filtered, concentrated at reduced pressure to first remove EtOAcfollowed by some DMF with pumping. The crude was dissolved in THF andthen preloaded by evaporation onto about 5 ml silica gel and thenchromatographed on 40 g silica gel using a gradient from 0-10% MeOH inCH₂Cl₂ to provide 457 mg (47.9%) of the desired product as a white solidalong with another 435 mg (46%) of mixed fractions contaminated with thedibromide which came from the tribromide contaminant in the startingmaterial as noted above in step 4. ¹H-NMR (DMSO-d₆) δ 7.86 (s, 1H), 6.65(s, 1H), 3.56 (t, 4H, J=4.6), 2.84 (t, 2H), 2.25-2.35 (m, 6H), and 1.80(pent, 2H, J=7.4); MS LC-MS [M+H]⁺=340.2/342.2, RT=1.09 min.

Intermediate W: Preparation of1-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanone

Step 1: Preparation of1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanone

To a suspension of pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.00 g, 7.46mmol) in nitrobenzene (40 mL) was added AlCl₃ (2.98 g, 22.36 mmol),followed by acetyl chloride (2.34 g, 29.82 mmol). The resulting solutionwas heated (60° C.) for 5 h and cooled to rt. The reaction mixture waspoured onto ice-water and solid sodium bicarbonate was added withstirring until the solution was basic. This mixture was extracted withethyl acetate (3×100 mL) and then the combined organic layers wereconcentrated under reduced pressure. The residue was stirred with MeOH(100 mL) and potassium carbonate (5 g) overnight. The solid was removedby filtration and the filtrate was concentrated under reduced pressure.The residue was purified by HPLC using a gradient of 5-30% MeCN in waterto afforded 448.0 mg (34%) of the title compound. ¹H-NNR (DMSO-d₆) δ9.63 (bs, 1H), 8.47 (bs, 1H), 8.03 (s, 1H), 7.76 (d, J=3.2 Hz, 1H), 7.40(d, J=2.9 Hz, 1H), 2.57 (s, 3H); MS [M+H]⁺=177.1; LCMS RT=1.37 min.

Step 2: Preparation of Title Compound

To a cooled (0° C.) solution of1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanone (262.0 mg, 1.49mmol) in DMF (21 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (212.6mg, 0.74 mmol). The mixture was stirred for 80 min and then quenched byaddition of saturated aqueous sodium sulphite (10 mL) and water (60 mL).The mixture was allowed to warm to rt and the precipitate was collectedby filtration. The solid was air-dried to yield 360.0 mg (95%) of thetitle compound. ¹H-NMR (DMSO-d₆) δ 9.49 (bs, 1H), 8.49 (bs, 1H), 8.12(s, 1H), 7.64 (s, 1H), 2.56 (s, 3H); MS [M+H]⁺=255.3; LCMS RT=1.96 min.

Intermediate X: Preparation of5-(4-aminophenyl)-7-(3-morpholin-4-ylpropyl)-pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate E, step 4 wasused to prepare the title compound by substituting Intermediate V(5-bromo-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine)for Intermediate C. ¹H-NMR (MeOH-d₄) δ 7.74(d, J=1 Hz, 1H), 7.17(dd,J=6, 2 Hz, 2H), 6.81(dd, J=6, 2 Hz, 2H), 3.67(t, J=5 Hz, 4H), 2.98 to2.91(m, 2H), 2.48 to 2.39(m, 6H), 1.98 to 1.91(m, 2H); MS [M+H]⁺=353.1;LCMS RT=1.03 min.

Intermediate Y:5-(4-amino-3-chlorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate F was used toprepare the title compound by substituting tert-butyl[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamatefor Intermediate P. MS [M+H]⁺=359; LCMS RT=1.30.

Intermediate Z:5-bromo-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Step 1: Preparation of7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

Pyrrolo[2,1-f][1,2,4]triazin-4-amine (4000 mg, 29.8 mmol) was dissolvedin acetic acid (160 mL). 37% wt formaldehyde in water is added (2.90 mL,35.8 mmol) followed by 1,4-oxazepane hydrochloride (4.92 g, 35.8 mmol)and potassium acetate (5.27 g, 53.7 mmol). The reaction was heated at60° C. under a nitrogen atmosphere overnight then cooled to roomtemperature. The reaction was concentrated under vacuum. The residue waspartitioned between EtOAc (300 mL) and saturated aqueous bicarbonate(150 mL). The aqueous layer is extracted with EtOAc (5×100 mL). Thecombined organics were washed with brine (100 mL) then dried with Na2SO4to yield 6.78 g (92%) of desired product.

¹H-NMR (DMSO-d₆) δ 7.80 (s, 1H), 7.63 (bs, 2H), 6.84 (d, J=4.5 Hz, 1H),6.54 (d, J=4.5, 1H), 3.64 (t, J=6 Hz, 2H), 3.55 (m, 2H), 2.63 (m, 4H),1.76 (m, 2H); MS [M+H]⁺=248.1; LCMS RT=1.02.

Step 2: Preparation of the Title Compound

7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.90 g,7.68 mmol) was suspended in chloroform (76 mL). The solution was cooledto −20 to −30° C. 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione ( 989g, 3.46 mmol) was added. The reaction was maintained at −20° C. for 20minutes then warmed to room temperature. An LC taken at that time showedthe reaction to be essentially complete. The reaction was then quenchedby the addition of saturated aqueous sodium sulfite. The resultantslurry was partitioned between ethyl acetate (300 mL) and saturatedbicarbonate (100 mL). The organic layer was washed (3×100 mL) withbicarb then dried with Na₂SO₄ and concentrated under vacuum.

The residue was triturated with ether to yield 2.09 g (83%) desiredproduct. ¹H-NMR (DMSO-d₆) δ 7.85 (s, 1H), 7.60 (bs, 2H), 6.72 (s, 1H),3.91 (s, 2H), 3.64 (m, 2H), 2.63 (m, 4H), 1.78 (m, 2H); MS [M+H]⁺=325.8;LCMS RT=1.07

Intermediate AA:1-[2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: 4-bromo-2-fluoro-5-methylaniline

To a slurry of 2-fluoro-5-metylaniline (6.75 g, 54 mmol) and CaCO₃ (10g, 100 mmol) in CH₂Cl₂ (1 L) and MeOH (400 mL) was added a solution ofBenzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH₂Cl₂ (180 mL)and MeOH (70 mL). The solution was added dropwise and the mixture wasstirred over night. The solution was a light orange/tan color. Themixture was filtered and the solvent was removed under reduced pressure.The resulting slurry was diluted with H₂O (100 mL) and extracted withEt₂O (3×200 mL). The mixture was purified by flash column chromatography(Hex:Et₂O 2:1 to Et₂O) to provide (9 g, 69.5% yield) the product as awhite solid. ¹H-NMR (DMSO-d₆) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H).

Step 2:1-(4-bromo-2-fluoro-5-methylphenyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of 4-bromo-2-fluoro-5-methylaniline (500 mg, 2.45 mmoL) inTHF (3 mL) was added the 2-fluoro-5-(trifluoromethyl)phenyl isocyanate(625 mg, 3.0 mmol). The reaction generated a white solid within 10 min.An additional portion of THF (3 mL) was added and the mixture dissolved.TLC analysis (1:1 Et₂O:Hex) indicated that the reaction was complete.The product was purified by flash column chromatography (Hex:Et₂O 2:1 toEt₂O). ¹H-NMR (DMSO-d₆) δ 9.37 (d, J=2.8 Hz, 1H), 9.17 (d, J=2.4 Hz,1H), 8.61 (dd, J=7.2, 2 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.55 (d, J=10.8Hz, 1H), 7.49 (dd, J=10.8, 8.8 Hz, 2H), 7.39 (m, 1H), 2.29 (s, 3H); MS[M+H]⁺=409.3, LCMS RT=3.91 min.

Step 3: Preparation of the Title Compound

To a solution of1-(4-bromo-2-fluoro-5-methylphenyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(300 mg, 0.73 mmol), bis(pinacolato)diboron (225 mg, 0.88 mmol) and KOAc(216 mg, 2.2 mmol) in Dioxane (10 mL) was added Pd(dppf)Cl₂ (27 mg, 0.04mmol). The reaction was capped and the heated to 85° C. and allowed tostir for 12 h. TLC analysis (3:1 Hex:EtOAc) indicated consumption ofstarting material. The compound was purified by flash columnchromatography to provide a white solid. ¹H-NMR (DMSO-d₆) δ 9.41 (d,J=2.8 Hz, 1H), 9.23 (d, J=2.8 Hz, 1H), 8.63 (dd, J=7.6, 2 Hz, 1H), 8.08(d, J=7.6 Hz, 1H), 7.46 (dd, J=10, 8 Hz, 1H), 7.37 (m, 3H), 7.30 (d,J=12 Hz, 1H), 2.42 (s, 3H), 1.27 (s, 12H); MS [M+H]⁺=457.2, LCMS RT=4.09min.

Intermediate AB: Preparation of tert-butyl3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate

Step 1: Preparation of tert-butyl3-(4-aminopyrrolo[2,1-t][1,2,4]triazin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

A 2L, 3-neck RB flask was fitted with a mechanical stirrer, a nitrogeninlet, thermocouple and thermocontroller, and a water cooling bath. Inthe flask, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (18.4 g, 86.3mmol) was suspended in tetrahydrofuran (250 mL) and treated withchlorotrimethylsilane (18.8 g, 172 mmol). The mixture was allowed tostir 16 h at rt. A solution of isopropylmagnesium chloride in THF (2M,173 mL, 345 mmol) was added slowly over 20 min taking care that theinternal temperature never rose above 40° C. After 1.5 h, a sample wasquenched in MeOH and analyzed by RP-HPLC indicated that the metallationwas 95% complete. The water bath was replaced with an ice-acetone bathand stirring was continued until the internal temperature fell to −10°C. tert-Butyl 3-oxopyrrolidine-1-carboxylate (20 g, 108 mmol) was addedas a solid, and the reaction was allowed to warm to rt over 30 min. Thereaction was again cooled to −10° C. and cautiously treated withtrifluoroacetic anhydride (45.4 g, 216 mmol), diisopropylethylamine(33.5 g, 259 mmol) and dimethylaminopyridine (527 mg, 4.3 mmol). Thereaction was warmed to rt and allowed to stir for 30 min, then treatedwith a 25% solution of NaOMe in MeOH (46 g, 215 mmol) and stirred for anadditional 15 min. The reaction was partitioned between EtOAc and 1N aqcitric acid. After 15 min stirring the organic layer was separated,washed with brine and dried with sodium sulfate. After filtering thesolution through a plug of silica, the filtrate was concentrated invacuo and the residue triturated with ethyl ether to provide the desiredproduct as a bright yellow solid (16.8 g, 65%). ¹H-NMR (DMSO): δ 7.72(dd, 1H), 7.61 (dd, 1H), 7.23 to 7.36 (m, 3H), 7.15 to 7.20 (m, 2H),6.96 (dd, 1H), 5.60 (s, 2H), 2.58 (s, 1H); MS: LC/MS (+esi): m/z=275.1[MH]⁺; LC/MS rt=3.51 min.

Step 2: Preparation of tert-butyl3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate

A suspension of platinum(IV) oxide (2.1 g, 9.5 mmol) and tert-butyl3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(11.4 g, 37.8 mmol) in AcOH (150 mL) was stirred for 16 h under a H₂atmosphere. The reaction was purged with N₂ and filtered throughCelite®, washing with AcOH. After removal of solvent in vacuo, theresidue was dissolved in THF:EtOAc and washed with saturated, aqueoussodium carbonate solution. The organic layer was dried and concentratedin vacuo to provide the desired product as a dark solid (10.7 g, 93%).MS: LC/MS (+esi): m/z=304.1 [MH]⁺; LC/MS rt=2.74 min.

Step 3: Preparation of the Title Compound

A solution of tert-butyl3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)pyrrolidine-1-carboxylate(1.2 g, 3.96 mmol) in DMF (20 mL) was cooled to 40° C. and treated with1,3-dibromo-5,5-dimethylhydantoin (508 mg, 1.78 mmol). The reaction wasallowed to warm slowly to rt over a 2 h period and was then partitionedbetween EtOAc and bicarbonate solution. After concentration, the residuewas triturated with EtOAc to yield the desired product (1.28 g, 85%).¹H-NMR (DMSO): δ 7.86 (s, 1H), 6.69 (s, 1H), 3.68 to 3.80 (m, 2H), 3.36to 3.46 (m, 1H), 3.20 to 3.30 (m, 2H), 2.16 to 2.30 (m, 1H), 1.98 to2.08 (m, 1H), 1.37 (s, 9H); MS: LC/MS (+esi), m/z=382.1 [M+H]; LC/MSrt=3.08 min.

Intermediate AC: Preparation of tert-butyl4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

Step 1: Preparation of tert-butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

To a stirred suspension of Intermediate B (523 mg, 2.46 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(Eastwood, P. R. Tetrahedron Lett. 2000, 41, 3705) (950 mg, 3.07 mmol),and 1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II)-complexwith dichloromethane (180 mg, 0.25 mmol) in degassed DME (18 mL) wasadded aqueous Na₂CO₃ solution (2 M, 3.7 mL). The reaction was heated(80° C.) for 17 h and then cooled to rt. The mixture was partitionedbetween ethyl acetate (50 mL) and H₂O (50 mL). The layers were separatedand the organic layer was washed with brine (25 mL), dried (Na₂SO₄), andconcentrated to dryness. The crude residue was purified by ISCO®chromatography using a gradient of 50 to 75% ethyl acetate in hexanes toafford 584 mg (75%) of the desired product as an off-white solid, whichcontained trace impurities. ¹H NMR (300 MHz, DMSO-d₆) δ 7.85 (s, 1H),7.68 (br s, 2H), 6.97 (br s, 1H), 6.87 (d, 1H), 6.66 (d, 1H), 4.07-4.00(m, 2H), 3.53 (t, 2H), 2.56-2.50 (m, 2H), 1.42 (s, 9H); ES-MS m/z 316.1[M+H]⁺, HPLC RT (min) 2.31.

Step 2: Preparation of tert-butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a dry flask purged with N₂ was added platinum(IV) oxide (127 mg, 0.56mmol) followed by tert-butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate(587 mg, 1.86 mmol) as a solution in acetic acid (19 mL). The mixturewas stirred under an H₂ atmosphere for 16 h. The mixture was filteredthrough a pad of Celite® rinsing with acetic acid and ethanol. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in ethyl acetate (100 mL). The organic was washed withsaturated aqueous NaHCO₃ (2×75 mL) and the aqueous mixture was backextracted with ethyl acetate (3×50 mL). The combined organics werewashed with brine, dried (Na₂SO₄) and concentrated to dryness to afford610 mg (100%) of the desired product as a gray solid.

¹H NMR (300 MHz, DMSO-d₆) δ 7.78 (s, 1H), 7.57 (br s, 2H), 6.78 (d, 1H),6.42 (d, 1H), 4.08-3.97 (m, 2H), 3.28-3.18 (m, 1H), 1.94 (d, 2H),1.55-1.42 (m, 2 H), 1.41 (s 9H); ES-MS m/z 318.1 [M+H]⁺, HPLC RT (min)2.21.

Step 3: Preparation of the Title Compound

To a cooled (−20° C.) solution of tert-butyl4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate(660 mg, 2.08 mmol) in tetrahydrofuran (10 mL) was added1,3-dibromo-5,5-dimethylhydantoin (297 mg, 1.04 mmol) in 3 portions over10 min. The mixture was allowed to stir (−20° C.) for 1 h. The reactionwas quenched with the addition saturated aqueous Na₂SO₃ (10 mL) and wasallowed to warm to rt. The mixture was extracted with ethyl acetate(3×20 mL). The combined organics were washed with brine (25 mL), dried(Na₂SO₄) and evaporated. The crude material was purified by ISCO®chromatography using a gradient of 75 to 100% ethyl acetate in hexanesto afford 494 mg (60%) of the desired product. ¹H NMR (300 MHz, DMSO-d₆)δ 7.83 (s, 1H), 6.64 (s, 1H), 4.10-3.96 (m, 2H), 3.29-3.19 (m, 1H), 1.90(d, 2H), 1.55-1.42 (m, 2H), 1.41 (s, 9H); ES-MS m/z 396.1 [M+]⁺, HPLC RT(min) 2.79.

The following boronates can be prepared in the same manner asIntermediate O by substituting the appropriate bromide forN-(4-bromo-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.Alternatively, they can be prepared in the same manner as IntermediateM, by substituting the appropriate aniline for4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and theappropriate isocyanate for 2-fluoro-5-trifluoromethyl phenylisocyante.Alternatively, they can be prepared in the same manner as IntermediateT, by substituting the appropriate aniline for2,5-difluoro-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline andthe appropriate carbamate forphenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate.

LC-MS m/z [M + H], RT, Int Structure IUPAC Name Method O

1-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5- (trifluoromethyl)phenyl]urea 443.3, 3.91 min, A AD

1-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2- yl]urea 407.9, 3.93 min, A AE

1-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin- 2-yl]urea 425.9, 4.17 min, A AF

1-[2-fluoro-5- (trifluoromethyl)phenyl]-3- [2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 439.2, 3.81 min, A AG

1-[2-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin- 2-yl]urea 422.2, 3.77 min, A AH

1-[2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [2-fluoro-5- (trifluoromethyl)phenyl]urea461.2, 4.38 min, A AI

1-(2-fluoro-5-methylphenyl)- 3-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 389.3, 3.83 min, A AJ

1-[2-chloro-5- (trifluoromethyl)phenyl]-3- [2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2- yl)phenyl]urea 459.1, 4.53 min, A N

1-[2-chloro-5- (trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)pheny]urea 441, 4.38min, A AK

2-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline 234.2,3.06 min, A P

tert-butyl [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamate 238.4 (M- Boc), 4.25 min, A T STEP 1

2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline256.3, 3.33 min, A M

1-[2-fluoro-5- (trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 425, 4.11min, A AL

1-[2-fluoro-5- (trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl]urea 509.3, 4.08 min, A AM

1-(4-tert-butylpyridin-2-yl)-3- [2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pheuyl]urea 414.3, 3.83 min, A Q

1-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[3- (trifluoromethyl)phenyl]urea 425.2, 4.24 min, A AN

1-[2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [3- (trifluoromethyl)phenyl]urea 443.2,4.26 min, A AO

1-(4-fluoro-3-methylphenyl)- 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 389.1, 4.06 min, A AP

1-[2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- (2-fluoro-5- methylphenyl)urea 406.9, 4.15min, A AQ

1-[2-chloro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[3- (trifluoromethyl)phenyl]urea 441.2 4.48 min, A AR

1-(3-ethylphenyl)-3-[4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]urea AS

1-(5-tert-butyl-2- fluorophenyl)-3-[2,5- difluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea AT

1-(2-fluoro-5-methylphenyl)- 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 370.9, 3.91 min, A AU

1-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]-3- [3- (trifluoromethyl)phenyl]urea 475.0, 4.38min, A AV

1-[2-chloro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5- (trifluoromethyl)phenyl]urea 459.2, 4.43 min, A AW

1-(3-tert-butylphenyl)-3-[2,5- difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 431.2, 4.57 min, A AX

1-[2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [4-fluoro-3- (trifluoromethyl)phenyl]urea461.1, 4.28 min, A AY

1-[2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [2-fluoro-3- (trifluoromethyl)phenyl]urea461.1, 4.28 min, A AZ

1-[2-chloro-5- (trifluoromethyl)phenyl]-3- 1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea BA

1-(3,4-dichlorophenyl)-3- [2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea BB

1-(4-tert-butylpyridin-2-yl)-3- [2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 432.2, 4.04 min, A T

1-[2,5-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [4-(trifluoromethyl)pyridin-2- yl]urea444.2, 4.24 min, A BC

1-(2-chloro-5-methylphenyl)- 3-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 4-5.4, 3.87 min, A BD

1-(4-fluoro-3-methylphenyl)- 3-[2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 389.1, 4.06 min, A BE

1-(3-ethylphenyl)-3-[2- fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]urea 385.1, 4.17 min, A BF

1-[2-fluoro-3- (trifluoromethyl)phenyl]-3-[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2- yl]urea426.3, 3.86 min, A BG

1-[3-fluoro-5- (trifiuoromethyl)phenyl]-3-[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2- yl]urea426.4, 3.88 min, A BH

1-[5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridin-2-yl]-3-[3-(trifluoromethyl)phenyl]urea 326.1 (—C₆H₁₀), 2.65 min, A BI

1-[4-chloro-3- (trifluoromethyl)phenyl]-3-[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2- yl]urea442.2, 4.19 min, A BJ

1-[4-fluoro-3- (trifluoromethyl)phenyl]-3-[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2- yl]urea426.1, 3.97 min, A BK

1-[5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyridin-2-yl]-3-[4-(trifluoromethyl)pyridin-2- yl]urea 409.1, 3.68 min, A BL

1-[2-fluoro-5- (trifluoromethyl)phenyl]-3-[5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2- yl]urea426.3, 4.17 min, A BM

1-[2,6-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [4-fluoro-3- (trifluoromethyl)phenyl]urea461.3, 3.92 min, A R

1-[2,6-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [2-fluoro-5- (trifluoromethyl)phenyl]urea461.2, 3.92 min, A S

1-[2,6-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [4-(trifluoromethyl)pyridin-2- yl]urea444.1, 4.00 min, A BN

1-[2,6-difluoro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3- [3- (trifluoromethyl)phenyl]urea 443.3,4.03 min, A BO

1-[4-chloro-3- (trifluoromethyl)phenyl]-3- [2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 477.2, 4.23 min, A BP

1-[2-fluoro-5- (trifluoromethyl)phenyl]-3- [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2- yl)phenyl]urea 439.2, 4.10 min, A BQ

2-fluoro-5-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 252.4 3.64 min, A BR

1-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl]-3-[3-(trifluoromethyl)phenyl]urea 406.8, 4.02 min, A U

1-[3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2- yl]urea 426.1, 4.04 min, A BS

1-[3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[3- (trifluoromethyl)phenyl]urea 425.2, 4.09 min, A BT

1-[3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5- (trifluoromethyl)phenyl]urea 443.1, 4.21 min, A BU

3-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline 234.3,2.93 min, A R STEP 1

2,6-difluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline256.3, 3.30 min, A BV

tert-butyl [2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamate 290.7, 4.37 min, A U STEP 1

3-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline 238.4,3.07 min, A BW

tert-butyl [2-methyl-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamate 234.1 (-Boc), 4.14 min, A BX

2-chloro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline 294.6(M + K), 3.51 min, A BY

2-fluoro-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)aniline 278.1(M + K), 3.35 min, A BZ

2-(3-fluoro-4-nitrophenyl)- 4,4,5,5-tetramethyl-1,3,2- dioxaborolaneKXG-220 No Ion! CA

tert-butyl [3-methoxy-4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamate ABF-1891 H-NMR

Example 1 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoro-methylphenyl]urea

To a solution of 1,4-dioxane (35 mL) was added Intermediate C (0.783 g,2.51 mmol) and Intermediate O (1.264 g, 2.88 mmol). The reaction mixturewas allowed to stir under nitrogen to dissolve and the reaction wasdegassed 5×. Sodium carbonate (1M, 7.5 mL) was added and the reactionwas degassed 5×. Finally tetrakis(triphenylphosphine)palladium(0) (0.290g, 0.25 mmol) is added and the reaction degassed 5× and then heated to80° C. overnight. After cooling to rt, the reaction mixture was dilutedwith EtOAc (300 ml) and washed 2× with saturated sodium bicarbonate, 1×brine, dried over sodium sulfate, filtered and concentrated to dryness.The residue dissolved was dissolved in THF (˜50 ml) and silicon thiol (2g, silicycle, 1.2 mmol/g loading) was added and stir vigorously for 90minutes. The silica gel derivative was removed by filtration and thefiltrate was purified via flash column (9:1 DCM:EtOH). The purifieddesired product was tritrated with DCM to obtain a white free flowingsolid (650 mg, 47.3% yield). ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.26 (s,1H), 8.65 (d, J=7.4 Hz 1H), 8.27 (t, J=8.6 Hz 1H), 7.91 (s, 1H), 7.51(t, J=9.7 Hz 1H), 7.42 to 7.38 (br m, 1H), 7.35 (d, J=12.4 Hz 1H), 7.24(d, J=8.4 Hz 1H), 6.67 (s, 1H), 3.81 (s, 2H), 3.55 (t, J=4.5 Hz 4H),2.44 (m, 4H); MS [M+H]⁺=548; LCMS RT=2.52 min

Example 2 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-tert-butylisoxazol-5-yl)urea

A mixture of Intermediate E (35 mg, 0.10 mmol),phenyl(3-tert-butylisoxazol-5-yl)carbamate (28 mg, 0.10 mmol) andtriethylamine(0.015 ml, 0.10 mmol) in THF (2 ml) was heated at 60° C.under N₂ for 16 h. Upon completion, the reaction was cooled to rt andthe solvent was evaporated. The resulting crude was purified via columnchromatography (95:5 v/v CH₂Cl₂—CH₃OH) to afford 21 mg of the titlecompound (yield 39%). ¹H-NMR (DMSO-d₆) δ 9.86 (s, 1H), 8.69 (s, 1H),7.63 (s, 1H), 7.30(d, J=8 Hz, 2H), 7.13(d, J=8 Hz, 2H), 6.36(s, 1H),5.80(s, 1H), 3.55(s, 2H), 3.29 to 3.12 (m, 4H), 2.19 to 2.16(m, 4H),1.05(s, 9H); MS [M+H]⁺=491.0; LCMS RT=2.24 min.

Example 3 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate H (phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate) forphenyl(3-tert-butylisoxazol-5-yl)carbamate. ¹H-NMR (DMSO-d₆) δ 9.86 (s,1H), 9.73 (s, 1H), 8.54 (d, J=5 Hz,1H), 8.05 (s, 1H), 7.63 (d, J=6 Hz,2H), 7.40(d, J=6 Hz, 2H) 7.34 (t, J=6 Hz,1H), 6.62(s, 1H), 3.81(s, 2H),3.55(t, J=4 Hz, 4H), 2.43(t, J=4 Hz, 4H); MS [M+H]⁺=513.0; LCMS RT=2.40min.

Example 4 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Intermediate E (37 mg, 0.11 mmol) in CH₂Cl₂ (3 ml) wasadded 2-fluoro-5-(trifluoromethyl)phenyl isocynate (48 mg, 0.22 mmol)and stirred at rt under N₂ for 16 h. Analytical HPLC showed all startingmaterials consumed. To the reaction mixture was added DMF (3 ml) and 2NHCl (0.07 ml, 0.14 mmol) and was heated at 80° C. for 3 h. Cooled to rt,the reaction solvent was evaporated partially. Diluted with ethylacetate (20 ml), the mixture was washed with aq. saturated NaHCO₃ andH₂O. After dried over Na₂SO₄, the crude product was concentrated andtriturated with CH₂Cl₂ (3×), hexane and ethyl ether (3×) to afford 27 mgof the title compound as a white solid (yield 45%). ¹H-NMR (DMSO-d₆) δ9.26 (s, 1H), 8.90 (s, 1H), 8.59 (dd, J=7, 3 Hz, 1H), 7.86 (s, 1H), 7.54(d, J=8 Hz, 2H), 7.47 to 7.35(m, 3H) 6.59(s, 1H), 3.78(s, 2H), 3.51(t,J=4 Hz, 4H), 2.43(t, J=4 Hz, 4H); MS [M+H]⁺=530.0; LCMS RT=2.45 min.

Example 5 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation Example 4 was used to prepare thetitle compound by substituting 3-trifluormethyl-phenylisocyanate for2-fluoro-5-(trifluoromethyl)-phenyl isocyanate. ¹R-NMR (CH₃OH-d₄) δ 7.92(s, 1H), 7.63 to 7.60 (m, 3H), 7.47 to 7.43 (m, 3H), 7.31 to 7.28(m,1H), 6.70 (s, 1H), 3.95(s, 2H), 3.69 (t, J=4 Hz, 4H), 2.59(t, J=4 Hz,1H); MS [M+H]⁺=511.9; LCMS RT=2.38 min.

Example 6 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 4-fluoro-3-(trifluoromethyl)phenylisocyanate for 2-fluoro-5-(trifluoromethyl)-phenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 9.06 (s, 1H), 8.93 (s, 1H), 8.02 to 7.99 (dd, J=7, 3 Hz,1H), 7.65 to 7.61 (m, 1H), 7.57 to 7.54 (dd, J=7 Hz, 2H), 7.43 to7.40(m, 1H), 7.40 to 7.36(dd, J=7, 2 Hz, 2H), 6.61(s, 1H), 3.80(s, 2H),3.53(t, J=4 Hz, 4H), 2.42(t, J=4 Hz, 4H); MS [M+H]⁺=529.9; LCMS RT=2.48min.

Example 7 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N′-[Z-fluoro-5-(trifluoro-methyl)phenyl]urea

Intermediate C (0.100 g, 0.32 mmol) and Intermediate R (0.176 g, 0.38mmol) were added as solids to a flask. Dioxane (17 mL) was then added tothe flask followed by 2N aqueous sodium carbonate (0.64 mmol, 0.32 uL).The reaction was degassed and tetrakis(triphenylphosphine) palladium (0)(0.037 g, 0.032 mmol) was added and the reaction was again placed undervacuum then blanketed with nitrogen. The reaction was heated at 80° C.until TLC showed the complete consumption of starting bromide (˜20h).The reaction was cooled to rt and EtOAc was added and washed with water.The combined organic layer was washed with brine, dried with Na₂SO₄ andconcentrated under vacuum. The residue was purified using silca gelcolumn chromatography (0-6% v/v MeOH(CH₂Cl₂) to afford the desiredproduct in 29% yield. ¹H-NMR (DMSO-d₆) δ 9.14 (d, J=3.3 Hz, 1H), 8.66(s,1H), 8.54 (d, J=7.2 Hz, 1H), 7.93 (s, 1H), 7.54-7.40 (m, 2H), 7.25(d, J=5.7 Hz, 2M), 6.75 (s, 1H), 3.81 (s,2H), 3.55 (t, J=4.5 Hz, 4H),2.44 (t, J=4.5 Hz, 4H); MS [M+H]⁺=566.1, LCMS RT=2.94 min.

Example 8 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 7 was used to preparethe title compound by substituting Intermediate AE for Intermediate R.The requisite boronate, was made using the procedure used to prepareIntermediate S, step1, followed by step 2 of the procedure used to makeIntermediate Q. ¹H-NMR (MeOD-d₄) δ 8.48 (d, J=5.4 Hz, 1H), 8.30 (t,J=8.1 Hz, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.33-7.25 (m, 3H), 6.71 (s,1H), 3.97 (s, 1H), 3.70 (t, J=4.2, 4H), 2.60 (t, J=4.5 Hz, 4H); MS[M+H]⁺=530.9, LCMS RT=2.33 min.

Example 9 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to Example 7 bysubstituting Intermediate BL for Intermediate R. ¹H-NMR (DMSO-d₆) δ10.07 (s, 1H), 8.68 (dd, J=6.9, 2.1, 1H), 8.32 (m,1H), 7.86-7.43 (m,3H), 7.91 (s, 1H, 3.81 (s, 2H), 3.55 (m, 4H), 2.44 (m, 4H); MS[M+H]⁺=531.0, LCMS RT=2.50 min.

Example 10 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The title compound was prepared by substituting Intermediate Q forIntermediate O in the procedure to make Example 1. ¹H-NMR (DMSO-d₆) δ9.43 (s, 1H), 8.73 (s,1H), 8.21 (t, J=8.4, 1H), 8.05 (s, 1H), 7.91(s,1H), 6.66 (s,1H) 3.81 (s, 2H), 3.54 (t, J=4.2 Hz, 4H), 2.44 (t, J=4.2Hz, 4H); MS [M+H]⁺=529.9, LCMS RT=2.47 min.

Example 11 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate U for Intermediate R. ¹H-NMR (DMSO-d₆) δ 10.04(s, 1H), 9.80 (s, 1H), 8.55 (m, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.66(dd, J=12.6 Hz, 2.1 Hz, 1H), 7.39-7.29 (m, 3H), 6.61 (s, 1H), 3.81 (s,2H), 3.54 (t, J=4.5, 4H), 2.43 (t, J=4.2 Hz, 4H); MS [M+H]⁺=531.0, LCMSRT=2.85 min.

Example 12 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to prepare Example 7by substituting Intermediate BK for Intermediate R. ¹H-NMR (DMSO-d₆) δ10.26 (s, 1H), 8.56 (d, J=5.1, 1H), 8.35 (s,1H), 8.22 (s, 1H), 7.92 (s,1H), 7.87-7.35 (m, 2H), 7.42 (dd, J=1.8, 0.6, 1H), 6.76 (s, 1H), 3.81(s, 2H), 3.54 (t, J=3.9 HZ, 4H), 2.44 (t, J=4.2, 4H); MS [M+H]⁺=513.9,LCMS RT=2.31 min.

Example 13 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting intermediate R with Intermediate T. NMR (DMSO-d₆) δ 10.19(m, 2H) 8.53 (d, J=5.1 Hz, 1H), 8.10 (dd, J=11.7, 5.1 1H), 8.00 (s, 1H),7.90 (s, 1H), 7.37-7.30 (m, 2H), 6.63 (s, 1H), 3.81 (s, 2H), 3.54 (t,J=3.6 Hz, 4H), 2.44 (t, J=4.5 Hz, 4H); MS [M+H]⁺=549.0, LCMS RT=2.48min.

Example 14 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate S for Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.95(s, 1H), 9.30 (s,1H), 8.50 (d, J=5.4, 1H) 7.97 (s, 1H), 7.92 (s,1H),7.32-7.20 (m,3H), 6.72 (s, 1H), 3.82 (s, 2H), 3.56 (m, 4H), 2.46 (m,4H)MS [M+H]⁺=549.0, LCMS RT=2.82 min.

Example 15 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate AH for Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.47(d, J=2.7, 1H), 9.43 (s, 1H), 8.63 (d, J=3.9 Hz, 1H), 8.15 (dd, 12.3Hz,7.2 Hz, 1H), 7.91 (s,1H) 7.55-7.42 (m, 2H), 7.32 (dd, J=11.7 Hz, 6.9Hz, 1H), 6.63 (s, 1H), 3.81 (s,2H), 3.54 (t, J=4.5, 4H), 2.43 (t, J=4.5,4H); MS [M+H]⁺=565.9, LCMS RT=2.75 min.

Example 16 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BT for Intermediate R. ¹H-NMR (MeOD-d₄) δ 8.59(m, 1H), 7.90 (s, 1H), 7.62 (d, J=10.2 Hz, 1H), 7.52-7.30 (m, 3H), 7.20(d, 1H), 6.60 (s, 1H), 3.53 (m, 4H), 2.35 (m, 4H); MS [M+H]⁺=547.9, LCMSRT=2.67 min.

Example 17 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BS for Intermediate R. ¹H-NMR (DMSO-d6) δ 9.15(s, 1H), 9.13 (s, 1H) 8.01 (s, 1H), 7.90 (s, 1h), 7.63-7.52 (m, 3h),7.35-7.23 (m, 3H) 6.60 (s, 1H) 3.81 (s, 2H), 3.57 (m, 4H), 2.45, (m,4h); MS [M+H]⁺=530.1, LCMS RT=2.56 min.

Example 18 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BJ for Intermediate R. ¹H-NMR (MeOD-d₄) δ 8.41(d, J=2.4 Hz, 1H), 7.94-7.73 (m, 4H), 7.32 (d, J=8.4 Hz, 1H), 7.22 (t,J=9.6, 1H), 6.86-6.66 (m, 2H), 3.99 (s, 2H), 3.68 (m, 4H), 2.57 (m, 4H)MS [M+H]+=531.0, LCMS RT=2.56 min.

Example 19 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BI for Intermediate R. ¹H-NMR (DMSO-d₆) δ10.95(s, 1H), 9.71 (s,1H) 8.67 (d, J=2.4, 1H),8.19 (d, J=2.7, 1H), 7.92 (s,1H), 7.82 (dd, J=8.7 Hz, J=2.4 Hz, 1H), 7.75 (dd, J=8.7 Hz, J=2.4 Hz,1H), 7.65 (d, J=9.3 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H) 6.68 (s, 1H),3.82(s, 2H), 3.54 (m, 4H), 2.40 (m, 4H); MS [M+H]+=547.0, LCMS RT=2.68 min.

Example 20 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BH for Intermediate R. ¹H-NMR (MeOD-d₄) δ 8.41(m, 1H) 7.96 (m, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.33 (d, J=8.7 Hz,1H), 7.23 (t, J=9.2 Hz, 1H), 6.86-6.64 (m, 2H) 5.39 (s, 2H), 3.95 (s,1H), 3.69 (m, 4H), 2.59, (m, 4H) MS [M+H]+=513.0, LCMS RT=2.52 min.

Example 21 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BF for Intermediate R. ¹H-NMR (DMSO-d₆) δ10.05 (s, 1H), 8.56 (m, 1H), 7.92 (s, 1H), 7.84 (dd, J=8.7 Hz, 2.4 Hz,1H) 7.41-7.38 (m, 3H), 6.70 (s, 1H), 3.82 (s, 2H), 3.58-3.53 (m, 4H),2.49-2.44 (m, 4H);MS [M+H]+=530.9, LCMS RT=2.42 min.

Example 22 Preparation ofN-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl)-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate BG for Intermediate R. ¹H-NMR (DMSO-d₆) δ11.18 (s, 1H), 9.46 (s, 1H), 9.80 (s,1H), 8.39 (d, J=1.8 Hz, 1H), 7.91(s,1H), 7.85-7.75 (m, 2H), 7.52 (d, J=9.6 Hz, 1H), 7.29 (d, J=3.6 Hz,1H), 6.68 (s,1H), 3.82 (s, 2H) 3.57 (m, 4H), 2.41 (m, 4H);MS [M+H+=531.1LCMS RT=2.81 min.

Example 23 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-4-fluoro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate AX for Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.46(s, 1H), 8.91 (s,1H), 8.49 (dd, J=11.7 Hz, J=6.9 Hz, 1H), 8.01 (m, 1H),7.91 (s, 1H), 7.61 (m, 1H), 7.46 (t, J=9.9 Hz, 1H) 7.31 (dd, 11.7 Hz,J=6.9 Hz, 1H) 6.63 (s, 1H), 3.80 (s, 2H), 3.54 (t, J=4.5 Hz, 4H) 2.43(t, J=4.5 Hz, 4H);MS [M+H]+=566.0 LCMS RT=2.75 min.

Example 24 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate AN for Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.48(s, 1H), 8.93 (s,1H), 8.12 (q, J=6.9 Hz, 1H), 8.04 (s, 1H), 7.91 (s,1H), 7.54 (d, J=5.1 Hz, 2H), 7.36-7.28 (m,3H), 6.63 (s, 1H), 3.81 (s,2H), 3.54 (t, J=4.5 Hz, 4H), 2.44 (t, J=4.5 Hz, 4H); MS [M+H]+=548.0LCMS RT=2.72 min.

Example 25 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,N-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[2-methyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]ureafor Intermediate R. The boronate, was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.66 (dd, J=4.2Hz, J=1.8 Hz, 1H) 8.57 (s, 1H) 7.99 (d, J=8.4, 1H) 7.89 (s, 1H), 7.50(m, 1H), 7.38 (m, 1H), 7.27 (m, 1H), 6.611 (s, 1H) 3.81 (s, 2H) 3.65(m,4H) 2.40 (m, 4H)); MS [M+H]+=544.1 LCMS RT=2.64 min

Example 26 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate AG for Intermediate R. ¹H-NMR (DMSO-d₆) δ10.16 (s, 1H), 9.9 (s, 1H), 8.55 (d, J=5.1 Hz, 1H), 8.09 (d. J=8.4, 1H)7.89 (s, 1H), 7.87 (s, 1H), 7.35 (m, 2H), 7.27 (dd, J=7.8 Hz, J=1.5 Hz,1H) 6.62 (s, 1H), 3.81 (s, 2H), 3.47 (m, 4H), 2.46 (m, 4H), 2.35 (s,3H); MS [M+H]+=527.1 LCMS RT=2.53 min

Example 27 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate, was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.56 (s, 1H), 8.21 (s, 1H),7.89-7.85 (m, 2H), 7.68 (s, 1H), 7.60 (d, J=11.4, 2H), 7.30 (s, 1H),7.27-7.23 (m, 2H), 6.61 (s, 1H), 3.81 (s, 2H), 3.54 (m, 4H), 2.43 (m,4H), 2.29 (s, 3H) MS [M+H]+=544.1 LCMS RT=2.64 min

Example 28 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,N-[3-fluoro-5-(trifluoromethyl)phenyl]-N′-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate, was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.57 (s, 1H),8.22 (s, 1H), 7.87(m, 2H), 7.60 (m, 2H), 7.26 (m, 2H), 6.61 (s, 1H), 3.81 (s, 2H), 3.64(m, 4H), 2.33 (m, 4H), 2.25 (s, 3H) ; MS [M+H]+=544.1 LCMS RT=2.70 min

Example 29 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate L for Intermediate E.¹H-NMR (DMSO-d₆) δ 9.26 (s, 1H), 8.92(d, J=3 Hz, 1H), 8.61(dd, J=8, 3Hz, 1H), 7.89(s, 1H), 7.56 to 7.32 (m, 4H), 7.20 (dd, J=8, 3 Hz, 1H),6.52 (s, 1H), 3.82(s, 2H), 3.46 (t, J=4 Hz, 4H), 2.44(t, J=4 Hz, 4H),2.14(s, 3H); MS [M+H]⁺=544.9; LCMS RT=2.49 min.

Example 30 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-(3-tert-butylisoxazol-5-yl)urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate K for Intermediate E.¹H-NMR (CH₃OH-d₄) δ 8.20(d, J=8 Hz, 1H), 7.83 (s, 1H), 7.10 to 7.02 (m,2H), 6.72 (s, 1H), 6.12 (s, 1H), 3.90 (s, 5H), 3.68 (t, J=5 Hz, 4H),2.56(t, J=5 Hz, 4H), 1.30(s, 9H); MS [M+H]⁺=520.8; LCMS RT=2.74 min.

Example 31 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate K for Intermediate E andsubstituting phenyl [4-(trifluoromethyl)pyridin-2-yl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate. ¹H-NMR (DMSO-d₆) δ 10.25(s,2H), 8.55(d, J=5 Hz, 1H), 8.25 (d, J=9 Hz, 1H), 7.88 (d, J=3 Hz, 2H),7.35 (d, J=3 Hz, 1H), 7.10 (d, J=2 Hz, 1H), 7.00(dd, J=8, 2 Hz, 1H),6.67 (s, 1H), 3.94(s, 3H), 3.81(s, 2H), 3.54 (m, 4H), 2.42(m, 4H); MS[M+H]⁺=543.1; LCMS RT=2.53 min.

Example 32 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate K for Intermediate E andby substituting phenyl [4-fluoro-3-(trifluoromethyl)phenyl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate.

¹H-NMR (DMSO-d₆) δ 9.69(s, 1H), 8.35(s, 1H), 8.19 (d, J=8 Hz, 1H), 8.01(dd, J=8, 2 Hz, 1H), 7.89 (s, 1H), 7.57 to 7.54(m, 1H), 7.43(t, J=9 Hz,1H), 7.08(d, J=2 Hz, 1H), 7.00 to 6.97 (dd, J=8, 2 Hz, 1H), 6.54(s, 1H),3.92(s, 3H), 3.81 (s, 2H), 3.54(t, J=4 Hz, 4H), 2.43(t, J=4 Hz, 4H); MS[M+H]⁺=560.2; LCMS RT=2.71 min.

Example 33 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[3-(trifluoromethoxy)phenyl]urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate K for Intermediate E andby substituting phenyl [4-fluoro-3-(trifluoromethoxy)phenyl]carbamatefor phenyl(3-tert-butylisoxazol-5-yl)carbamate. ¹H-NMR (MeOH-d₄) δ8.18(d, J=4 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.65 to 7.63 (m, 1H),7.38 to 7.30 (m, 2H), 7.29 to 7.26(m, 2H), 7.09 to 7.02(m, 2H), 6.91 to6.64 (m, 4H), 3.94(s, 3H), 3.87(s, 2H), 3.31 (m, 4H), 2.58(m, 4H); MS[M+H]⁺=558.1; LCMS RT=2.77 min.

Example 34 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl]-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate K for Intermediate E andby substituting phenyl [4-chloro-3-(trifluoromethyl)phenyl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate.

¹H-NMR (MeOH-d₄) δ 8.18(d, J=8 Hz, 1H), 8.02 (d, J=3 Hz, 1H), 7.83(s,1H), 7.63 to 7.59 (m, 1H), 7.48 (d, J=8 Hz, 1H), 7.10(d, J=2 Hz, 1H),7.02(dd, J=8, 2 Hz, H), 6.72 (s, 1H), 3.97(s, 3H), 3.96(s, 2H), 3.68(t,J=5 Hz, 4H), 2.58(t, J=5 Hz, 4H); MS [M+H]⁺=576.1; LCMS RT=2.81 min.

Example 35 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate K for Intermediate E andby substituting 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene for2-fluoro-5-(trifluoromethyl)phenyl isocynate. ¹H-NMR (DMSO-d₆) δ 9.28(d,J=3 Hz, 2H), 8.59 (d, J=3 Hz, 1H), 8.17(d, J=8 Hz, 1H), 7.89(s, 1H),7.70(dd, J=8, 3 Hz, 1H), 7.37 (dd, J=8, 3 Hz, 1H), 7.10 (d, J=3 Hz, 1H),7.03 (dd, J=8, 2 Hz, 1H), 6.67 (s, 1H), 3.92(s, 3H), 3.81(s, 2H),3.54(t, J=4 Hz, 4H), 2.43(t, J=4 Hz, 4H); MS [M+H]⁺=576.0; LCMS RT=2.98min.

Example 36 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate K for Intermediate E.¹H-NMR (DMSO-d₆) δ 9.61(d, J=3 Hz, 1H), 9.00 (s, 1H), 8.17(dd, J=8, 2Hz, 1H), 8.22(d, J=8 Hz, 1H), 7.89(s, 1H), 7.51 to 7.45 (m, 1H), 7.39 to7.34(m, 1H), 7.09(d, J=5 Hz, 1H), 7.00(dd, J=8, 2 Hz, 1H), 6.67 (s, 1H),3.92(s, 3H), 3.81(s, 2H), 3.54(t, J=4 Hz, 4H), 2.43(t, J=4 Hz, 4H); MS[M+H]⁺=559.9; LCMS RT=2.56 min.

Example 37 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4-triazin-5-yl]-3-methoxyphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,N-[2-fluoro-5-(trifluoromethyl)phenyl]-N′-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate, was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.93 (m, 1H), 8.62(dd, J=7.2 Hz, J=1.8 Hz, 1H), 7.54 (s, 1H), 7.49 (m, 1H), 7.40 (s, 1H),7.18 (d, J=7.8 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.01 (m, 1H), 6.50(s,1H), 3.78 (s, 2H), 3.62 (s, 3H), 3.54 (m, 4H), 2.43 (m, 4H); MS[M+H]+=559.8, 560.9 LCMS RT=2.44 min

Example 38 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methoxyphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make example 7 bysubstituting boronate,N-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]ureafor Intermediate R. The boronate, was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.85 (s, 1H), 9.71 (s, 1H), 8.54(d, J=5.4, 1H), 8.06 (s, 1H), 7.84(s, 1H), 7.42 (s, 1H), 7.36 (d, J=5.4Hz, 1H), 7.18 (d, J=5.4 Hz, 1H) 7.09 (m, 1H), 6.50 (s, 1H), 3.79 (s,2H), 3.72 (s, 3H),3.50 (m, 4H), 2.41 (m, 4H); MS [M+H]+=543.5 LCMSRT=2.49 min

Example 39 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A solution of Intermediate D (70 mg, 0.215 mmol) and Intermediate M (100mg, 0.237 mmol) in 1,4-dioxane (2.0 ml) was degassed 3 times by pullinga vacuum and then releasing to a nitrogen stream. Aqueous Na₂CO₃ (0.646ml, 1 M, 0.646 mmol) was added and the mixture was degassed again.Tetrakis(triphenylphosphine)palladium (0) (25 mg, 0.022 mmol) was addedand the mixture was again degassed followed by addition of another 1 mlof 1,4-dioxane to rinse down solids from the sidewalls of the reactionvial. This vial was sealed under nitrogen with a septa cap and heatedwith stirring at 80° C. for 13.5 hours. The resultant mixture wasdiluted with EtOAc, washed with saturated aqueous NaHCO3 and with brine,dried (Na2SO4) and evaporated in vacuo. The residue was chromatographedon 12 g of silica gel using a gradient from 0-10% MeOH in CH2Cl2 to givepure title

Example 40 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 39 was used to preparethe title compound by substituting Intermediate O for Intermediate M.¹H-NMR (DMSO-d₆) δ 9.40(d, J=3 Hz, 1H), 9.24(d, J=3 Hz, 1H), 8.64(dd,J=7, 3 Hz, 1H), 8.25(t, J=7 Hz, 1H), 7.91(s, 1H), 7.52(t, J=7 Hz, 1H),7.46 to 7.32 (m, 2H), 7.25 (dd, J=8, 3 Hz, 1H), 6.70 (s, 1H), 3.90(s,2H), 3.11 (m, 4H), 2.98(s, 2H), 2.60(t, J=5 Hz, 2H); MS [M+H]⁺=560.8;LCMS RT=2.51 min.

Example 41 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared using the procedure to make Example 39by substituting boronate, Intermediate AD for Intermediate M. ¹H-NMR(DMSO-d₆) δ 9.89 (s, 1H), 9.76 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.06 (S,1H), 7.90 (s,1H), 7.71 (bs, 1H), 7.61 (d, J=6.9 Hz, 2H), 7.42 (d, J=6.9Hz, 2H), 7.36 (m, 1H), 6.67 (s, 1H), 3.91 (s, 2H), 3.27 (m, 2H), 3.11(s, 2H), 2.62 (m, 2H); MS [M+H]+=526.0 LCMS RT=2.37 min

Example 42 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting Intermediate AX for Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.39(m, 1H), 8.26 (m, 1H), 8.10 (m, 1H), 7.90 (s, 1H), 7.37 (m, 2H), 7.07(m, 1H), 6.62 (m, 2H); MS [M+H]+=566.8

Example 43 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 2was used to preparethe title compound by substituting Intermediate K for Intermediate E andsubstituting phenyl [6-(trifluoromethyl)pyridin-2-yl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate. ¹H-NMR (DMSO-d₆) δ 10.33 (s,1H), 10.09 (br, 1H), 8.25 (d, J=8 Hz, 1H), 8.03 (m, 1H), 7.89 (s, 1H),7.73 (d, J=8 Hz, 1H), 7.48 (d, J=7 Hz, 1H), 7.10(d, J=2 Hz, 1H),7.00(dd, J=8, 2 Hz, 1H), 6.67 (s, 1H), 3.90(s, 3H), 3.81(s, 2H), 3.54(m, 4H), 2.42(m, 4H); MS [M+H]⁺=543.0; LCMS RT=2.53 min.

Example 44 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-tert-butyl-2-methoxyphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 5-tert-butyl-2-methoxyphenylisocyanate for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 9.40 (s, 1H), 8.29 (s, 1H), 8.20 (s, 1H), 7.86 (s, 1H), 7.59(d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.82-6.95 (m, 2H), 6.60 (s,1H), 3.85 (s, 3H), 3.82 (s, 2H), 3.48-3.60 (m, 4H), 2.38-2.2.5 (m, 1.28(s, 9H); MS [M+H]⁺=530; LCMS RT=2.57.

Example 45 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2,5-dimethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 2,5-dimethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.17 (s,1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 7.55 (d, J=8.8 Hz, 2H),7.35 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.0 Hz, 1H ), 6.75 (d, J=8.0 Hz, 1H),6.61 (s, 1H), 3.82 (s, 2H), 3.56-3.54 (m, 4H), 2.49-2.44 (m, 4H), 2.25(s, 3H), 2.20 (s, 3H); MS [M+H]⁺=472.2; LCMS RT=2.29.

Example 46 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 2-fluoro-5-methylphenyl isocyanatefor 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.17(s, 1H), 8.50 (d, J=2.4, 1H), 7.97 (dd, J=8.4, 2.8 Hz, 1H), 7.88 (s,1H), 7.54 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H), 7.09 (dd, J=11.6,8.0 Hz, 1H), 6.82-6.75 (m, 1H), 6.61 (s, 1H), 3.82 (s, 2H), 3.55 (t,J=4.4 Hz, 4H), 2.48 (t, J=4.4 Hz, 4H), 2.72 (s, 3H); MS [M+H]⁺=476; LCMSRT=2.22.

Example 47 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-methylpyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl(5-methylpyridin-2-yl)carbamate for 2-fluoro-5-trifluoromethylphenylisocyanate. ¹H-NMR (DMSO-d₆) δ 10.60 (s, 1H), 9.38 (s, 1H), 8.10 (s,1H), 7.88 (s, 1H), 7.62-7.55 (m, 3H), 7.40-7.37 (m, 3H),6.62 (s, 1H),3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t, J=4.4 Hz, 4H), 2.23 (s,3H); MS [M+H]⁺=459; LCMS RT=1.77.

Example 48 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-methylphenyl)ureahydrochloride

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3-methylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 8.78 (s,1H), 8.63 (s, 1H), 7.89 (s, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 7.3 (s, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.15 (t, J=7.6 Hz, 1H),6.78 (t, J=6.8 Hz, 1H) 6.61 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz,4H), 2.45 (t, J=4.4 Hz, 4H), 2.27 (s, 3H); MS [M+H]⁺=458; LCMS RT=1.70.

Example 49 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-tert-butylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 2-tert-butylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.32 (s,1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.57 (d, J=6.8 Hz, 2H), 7.38-7.34 (m,3H), 7.27 (dd, J=7.6, 1.6 Hz, 1H), 7.22-7.14 (m, 2H), 6.61 (s, 1H), 3.82(s, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t, J=4.4 Hz, 4H), 1.38 (s, 9H);MS [M+H]⁺=500.3; LCMS RT=2.34.

Example 50 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-ethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3-ethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 8.88 (s,1H), 8.74 (s, 1H), 7.90 (s, 1H), 7.56 (d, J=7.6 Hz, 2H), 7.37 (d, J=7.6Hz, 2H), 7.33 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H),6.82 (d, J=7.6 Hz, 1H), 6.62 (s, 1H) 3.82 (s, 2H), 3.55 (t, J=4.4 Hz,4H), 2.56 (q, J=7.6 Hz, 2H), 2.45 (t, J=4.4 Hz, 4H), 1.17 (t, J=7.6 Hz,3H); MS [M+H]⁺=472.2; LCMS RT=2.33.

Example 51 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3-fluoro-5-(trifluoromethyl)phenylisocyanate for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 9.39 (s, 1H), 9.22 (s, 1H), 7.90 (s, 1H), 7.72 (s, 1H), 7.63(d, J=10.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.23(d, J=10.4 Hz, 1H),6.63 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H),2.45 (t, J=4.4 Hz, 4H); MS [M+H]⁺=529.9; LCMS RT=2.64.

Example 52 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 2-chloro-5-(trifluoromethyl)phenylisocyanate for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 9.74 (s, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 7.90 (s, 1H), 7.73(d, J=8.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz 2H), 7.38(s, 1H), 6.63 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t,J=4.4 Hz, 4H); MS [M+H]⁺=546; LCMS RT=2.98.

Example 53 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(4-tert-butylpyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl 4-tert-butylpyridin-2-ylcarbamate for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 10.89 (s, 1H), 9.45 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.90(s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 7.40 (d, J=8.8 Hz, 2H),7.07 (d, J=5.6 Hz, 1H) 6.63 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz,4H), 2.45 (t, J=4.4 Hz, 4H), 1.26 (s, 9H); MS [M+H]⁺=501.1; LCMSRT=2.65.

Example 54 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 4-chloro-3-(trifluoromethyl)phenylisocyanate for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 9.25 (s, 1H), 9.02 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.90 (s,1H), 7.64-7.58 (m, 2H), 7.57 (d, J=7.6 Hz, 2H), 7.39 (d, J=7.6 Hz, 2H),6.63 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t, J=4.4 Hz,4H); MS [M+H]⁺=546.1; LCMS RT=3.00.

Example 55 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-(5-fluoropyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl 5-fluoropyridin-2-yl carbamatefor 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.95(s, 1H), 9.44 (s, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.75-7.70 (m, 2H),7.60 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 6.63 (s, 1H), 3.82 (s,2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t, J=4.4 Hz, 4H); MS [M+H]⁺=463; LCMSRT=2.17.

Example 56 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[5-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl5-(trifluoromethyl)pyridin-2-yl carbamate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 10.14(s, 1H), 9.87 (s, 1H), 8.67 (s, 1H), 8.14 (dd, J=8.8, 3.2 Hz, 1H), 7.90(s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8Hz, 2H), 6.63 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t,J=4.4 Hz, 4H); MS [M+H]⁺=513; LCMS RT=2.46.

Example 57 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-(6-methylpyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl 6-methylpyridin-2-yl carbamatefor 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.55(s, 1H), 7.91 (s, 1H), 7.66-7.62 (m, 3H), 7.63 (d, J=8.4 Hz, 2H), 7.20(d, J=8.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 2H),), 6.63 (s, 1H), 3.82 (s, 2H),3.55 (t, J=4.4 Hz, 4H), 2.46 (s, 3H), 2.45 (t, J=4.4 Hz, 4H); MS[M+H]⁺=459; LCMS RT=0.72.

Example 58 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 2-fluoro-3-(trifluoromethyl)phenylisocyanate for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 11.70 (s, 1H), 9.55 (s, 1H), 9.07 (s, 1H), 8.51-8.42 (m,1H), 7.89 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.40-7.35 (m, 3H), 6.62 (s,1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.45 (t, J=4.4 Hz, 4H); MS[M+H]⁺=529.9; LCMS RT=2.97.

Example 59 Preparation ofN-(3-acetylphenyl)-N′-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3-acetylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.13 (s,1H), 9.06 (s, 1H), 8.11 (t, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.66-7.58 (m,4H), 7.44 (d, J=7.6 Hz, 2H), 7.42 to 7.38 (m, 1H), 6.92 (s, 1H), 4.72(s, 2H), 4.02-3.94 (m, 2H), 3.68-3.59 (m, 2H), 3.42-3.35 (m, 2H),3.38-3.15 (m, 2H), 2.56 (s, 3H); MS [M+H]⁺=486; LCMS RT=0.63.

Example 60 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-(3,4-dimethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3,4-dimethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 8.84 (s,1H), 8.60 (s, 1H), 8.05 (s, 1H), 7.58 (d, J=6.8 Hz, 2H), 7.37 (d, J=6.8Hz, 2H), 7.23 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H),6.91 (s, 1H), 4.71 (s, 2H), 4.02-3.94 (m, 2H), 3.68-3.59 (m, 2H),3.42-3.35 (m, 2H), 3.38-3.15 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H); MS[M+H]⁺=472.1; LCMS RT=2.53.

Example 61 Preparation ofN-{4-(4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-(3,5-dimethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3,5-dimethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.01 (s,1H), 8.76 (s, 1H), 8.06 (s, 1H), 7.59 (d, J=9.2 Hz, 2H), 7.37 (d, J=9.2Hz, 2H), 7.08 (s, 2H), 6.92 (s, 1H), 6.61 (s, 1H), 4.72 (s, 2H),4.08-3.15 (m, 8H), 2.22 (s, 6H); MS [M+H]⁺=472.1; LCMS RT=2.64.

Example 62 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-(3-chloro-4-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 3-chloromethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 8.99 (s,1H), 8.94 (s, 1H), 8.05 (s, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.59 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.8 Hz, 1H), 7.19 (dd,J=8.4, 2.4 Hz, 1H), 6.92 (s, 1H), 4.71 (s, 2H), 4.08-3.15 (m, 8H), 2.25(s, 3H); MS [M+H]⁺=492.1; LCMS RT=2.85.

Example 63 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-chloropyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl 5-chloropyridin-2-yl carbamatefor 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR DMSO-d₆) δ 9.93(s, 1H), 9.51 (s, 1H), 8.31 (d, J=2.8 Hz, 1H), 7.88 (s, 1H), 7.60 (dd,J=9.2, 2.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.39(d, J=8.4 Hz, 2H), 6.62 (s, 1H), 3.82 (s, 2H), 3.55 (t, J=4.4 Hz, 4H),2.45 (t, J=4.4 Hz, 4H); MS [M+H]⁺=478.9; LCMS RT=2.27.

Example 64N-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-(3-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate F andby substituting 3-methylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.09 (s,1H), 8.72 (d, J=2.8 Hz, 1H), 8.32 (t, J=8.4 Hz, 1H), 8.09 (s, 1H), 7.35(dd, J=11.6, 2 Hz, 1H); 7.32 (d, J=2.8 Hz, 1H), 7.26 (m, 2H) 7.19 (t,J=8.4 Hz, 1H), 6.97 (s, 1H), 6.83 (m 1H), 4.73 (s, 2H), 3.97 (m, 2H),3.64 (m, 2H), 3.38 (m, 2H), 3.22 (m, 2H), 2.30 (s, 3H); MS [M+H]⁺=476.1;LCMS RT=2.35.

Example 65N-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate F andby substituting 2chloro-5-(trifluoromethyl)phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.64 (d,J=2.4 Hz, 1H), 9.15 (s, 1H), 8.66 (d, J=2 Hz, 1H), 8.28 (t, J=8.8 Hz,1H), 7.93 (s, 1H), 7.74 (d, J=8 Hz, 1H), 7.40 (dd, J=8.4, 2.0 Hz, 1H),7.37 (dd, J=12.4, 2.0 Hz, 1H), 7.26 (dd, J=8.4, 1H), 3.83 (s, 2H), 3.56(m, 4H), 2.46 (m, 4H); MS [M+H]⁺=564.0; LCMS RT=2.70.

Example 66N-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-(3-chlorophenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate F andby substituting 3chloro-phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR DMSO-d₆) δ 9.45 (s,1H), 8.85 (s, 1H), 8.23 (t, J=8.4 Hz, 1H), 7.96 (s, 1H), 7.78 (t, J=2Hz, 1H), 7.38-7.25 (m, 3H), 7.07 (m, 1H), 3.90 (s, 2H), 3.45 (m, 4H),2.45 (m, 4H); MS [M+H]⁺=495.9; LCMS RT=2.39.

Example 67N-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-(3-bromophenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate F andby substituting 3-bromo-phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.40 (s,1H), 8.85 (d, J=2.4 Hz, 1H), 8.27 (t, J=8.8 Hz, 1H), 8.10 (s, 1H), 7.92(m, 1H), 7.36 (dd, J=12.0, 2.0 Hz, 1H), 7.32-7.25 (m, 3H), 7.19 (dt,J=7.2, 2.0 Hz, 1H), 6.98 (s, 1H), 4.73 (s, 2H), 3.95 (m, 2H), 3.67 (m,2H), 3.38 (m, 2H), 3.22 (m, 2H); MS [M+H]⁺=453.2; LCMS RT=2.50.

Example 68 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting phenyl(6-trifluoromethyl)pyridin-2-yl carbamate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.92 (s,1H), 9.78 (s, 1H), 8.05-7.99 (m, 3H), 7.60 (d, J=8.8 Hz, 2H), 7.51 (d,J=7.6 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 6.62 (s, 1H), 3.80 (s, 2H),3.58-3.50 (m, 4H), 2.46-2.38 (m, 4H); MS [M+H]⁺=513; LCMS RT=2.41.

Example 69 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-(6-bromopyridin-2-yl)urea

The procedure used for the preparation of Example 4was used to preparethe title compound by substituting (6-bromo-pyridin-2-yl)-carbamic acidphenyl ester for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 9.95 (s, 1H), 9.83 (s, 1H), 7.89 (s, 1H), 7.79 (d, J=8.4,1H), 7.65 (t, J=8.4, 1H), 7.59 (d, J=8.8, 2H), 7.39 (d, J=8.8, 2H), 7.21(d, J=8.4, 1H), 6.62 (s, 1H), 3.81 (s, 2H), 3.58 (t, J=2.4, 4H), 2.44(s, 4H); MS [M+H]⁺=523; LCMS RT=2.30.

Example 70 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-(6-methoxypyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting (6-methoxy-pyridin-2-yl)-carbamicacid phenyl ester for 2-fluoro-5-trifluoromethylphenyl isocyanate.¹H-NMR (DMSO-d₆) δ 9.95 (s, 1H), 9.28 (s, 1H), 7.90 (s, 1H), 7.63 (t,J=8.4, 1H), 7.60 (d, J=8.4, 2H), 7.40 (d, J=8.4, 2H), 7.19 (d, J=8.8,1H), 6.61 (s, 1H) 6.43 (d, J=8.8, 1H), 3.90 (s, 3H), 3.83 (s, 2H), 3.58(t, J=2.4, 4H), 2.43-2.40 (br, 4H); MS [M+H]⁺=475; LCMS RT=2.11.

Example 71 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-(6-ethylpyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting (6-ethyl-pyridin-2-yl)-carbamic acidphenyl ester for 2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR(DMSO-d₆) δ 11.11 (s, 1H), 9.58 (s, 1H), 7.89 (s, 1H), 7.69-7.60 (m,3H), 7.40 (d, J=8.4, 2H), 7.19 (d, J=8.4, 1H), 6.85 (d, J=8.4, 1H), 6.61(s, 1H), 3.82 (s, 2H), 3.55 (t, J=2.4, 4H), 2.78 (q, J=2.8, 2H), 2.42(s, 4H), 1.25 (t, J=2.8, 3H); MS [M+H]⁺=473; LCMS RT=2.00.

Example 72 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-(6-methoxypyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate F andby substituting (6-methoxy-pyridin-2-yl)-carbamic acid phenyl ester for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 10.10(s, 1H), 9.92 (s, 1H), 8.25 (t, J=8.8, 1H), 7.91 (s, 1H), 7.72 (t,J=8.8, 1H), 7.63 (d, J=8.8, 1H), 7.35 (d, J=8.8, 1H), 7.32-7.28 (m, 2H),6.66 (s, 1H), 3.81 (s, 2H), 3.57 (s, 4H), 3.40 (s, 3H), 2.41 (s, 4H); MS[M+H]⁺=493; LCMS RT=2.25.

Example 73 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]-2-fluorophenyl-N′-(6-bromopyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate F andby substituting (6-methoxy-pyridin-2-yl)-carbamic acid phenyl ester for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.95 (s,1H), 9.73 (s, 1H), 8.26 (t, J=8.8, 1H), 7.92 (s, 1H), 7.65 (t, J=8.8,1H), 7.38 (d, J=8.8, 1H), 7.25 (d, J=8.8, 1H), 7.20 (d, J=8.8, 1H), 6.67(s, 1H), 6.42 (d, J=8.8, 1H), 3.83 (s, 2H), 3.59 (t, J=2.8, 4H), 2.43(s, 4H); MS [M+H]⁺=541; LCMS RT=2.45.

Example 74 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-(3-phenoxyphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting (6-phenoxy-pyridin-2-yl)-carbamicacid phenyl ester for 2-fluoro-5-trifluoromethylphenyl isocyanate.¹H-NMR (DMSO-d₆) δ 9.58 (s, 1H), 9.50 (s, 1H), 7.88 (s, 1H), 7.58 (d,J=8.8, 2H), 7.41-7.30 (m, 4H), 7.26 (t, J=8.8, 1H), 7.19-7.10 (m, 2H),7.02 (d, J=8.8, 2H), 6.62-6.58 (m, 2H), 3.82 (s, 2H), 3.55 (t, J=2.8,4H), 2.42 (s, 4H); MS [M+H]⁺=537; LCMS RT=2.53.

Example 75 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-ethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate G andby substituting 3-ethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.04 (s,1H), 8.62 (d, J=2.8, 1H), 8.25 (t, J=8.4, 1H), 7.91 (s, 1H); 7.33 to7.30 (m, 2H), 7.25 to 7.16 (m, 3H), 6.83 (d, J=7.2,1H), 6.73 (s, 1H),4.02 (s, 2H), 3.10 (d, J=5.2, 4H), 2.95 (d, J=2.8, 4H), 2.56 (q, J=7.6,2H), 1.16 (t, J=7.2, 3H); MS [M+H]⁺=539.0; LCMS RT=3.34.

Example 76 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate B for Intermediate G andby substituting 3-methylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.02 (s,1H), 8.63 (d, J=2.0, 1H), 8.25 (t, J=8.8, 1H), 7.91 (s, 1H); 7.34 to7.30 (m, 2H), 7.23 to 7.14 (m, 3H), 6.82 (d, J=7.2, 1H), 6.73 (s, 1H),4.02 (s, 2H), 3.11 (d, J=5.2, 4H), 2.94 (d, J=2.7, 4H), 2.27 (s, 3H); MS[M+H]⁺=524.0; LCMS RT=3.19.

Example 77 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate B for Intermediate G andby substituting 3-trifluoromethylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.45 (s,1H), 8.76 (s, 1H), 8.22 (t, J=8.4, 1H); 8.05 (s, 1H), 7.92 (s, 1H), 7.53(dd, J=4.8, 1.2, 2H), 7.36 to 7.32 (m, 2H), 7.24 (dd, J=8.4, 1.2, 1H),6.74 (s, 1H), 4.03 (s, 2H), 3.12 to 3.10 (m, 4H), 2.95 to 2.94 (m, 4H);MS [M+H]⁺=577.9; LCMS

Example 78 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate G andby substituting Intermediate H for 2-fluoro-5-trifluoromethylphenylisocyanate ¹H-NMR (DMSO-d₆) δ 10.16 (s, 1H), 10.11 to 10.09 (m, 1H),8.57 (d, J=5.2, 1H); 8.30 (t, J=8.4, 1H), 8.03 (s, 1H), 7.95 (s, 1H),7.41 to 7.38 (m, 2H), 7.29 (d, J=8.8, 1H), 6.77 (s, 1H), 4.06 (s, 2H),3.16 to 3.12 (m, 4H), 3.00 to 2.96 (m, 4H); MS [M+H]⁺=580.9; LCMSRT=2.67.

Example 79 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate E for Intermediate G.¹H-NMR (DMSO-d₆) δ 9.42 to 9.40 (m, 1H), 9.27 to 9.25 (m, 1H), 8.65 (dd,J=7.2, 2.0, 1H); 8.27 (t, J=8.8, 1H), 7.92 (s, 1H), 7.51 (t, J=8.8, 1H),7.42 to 7.38 (m, 1H), 7.35 (dd, J=12.0, 1.6, 1H), 7.25 (dd, J=7.6, 2.0,1H), 6.74 (s, 1H), 4.03 (s, 2H), 3.13 to 3.09 (m, 4H), 2.96 to 2.93 (m,4H); MS [M+H]⁺=595.9; LCMS RT=2.80.

Example 80 Preparation of tert-butyl4-[(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate I for Intermediate E.¹H-NMR (DMSO-d₆) δ 9.29(s, 1H), 8.93 (d, J=3 Hz, 1H), 8.62 (dd, J=5, 2Hz, 1H), 7.89 (s, 1H), 7.57 (dd, J=5, 2 Hz, 1H), 7.53 to 7.46(m, 4H),6.62(s, 1H), 3.83(s, 2H), 3.29(m, 4H), 2.39(t, J=5 Hz, 4H), 1.35(s, 9H);MS [M+H]⁺=629.0; LCMS RT=2.82 min.

Example 81 Preparation ofN-4-[4-amino-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 80 (100 mg, 0.13 mmol) in CH₂Cl₂ (5 ml) wasadded TFA (1.6 ml) and 2N HCl (1 ml) and stirred at rt for 48 h. Thereaction mixture was partially evaporated and ethyl acetate (10 ml) wasadded and washed with saturated aq. NaHCO₃. The organic was dried overNa₂SO₄ and concentrated to afford 60 mg of the title compound (yield85%). ¹H-NMR (MeOH-d₄) δ 8.60 (dd, J=7, 1 Hz, 1H), 7.97 (s, 1H), 7.83(s, 1H), 7.60(m, 2H), 7.45 to 7.42 (m, 2H), 7.35 to 7.32(m, 2H), 6.69(s,2H), 3.96(s, 2H), 3.66(t, J=4 Hz, 1H), 2.87 to 2.84(t, J=4 Hz, 4H),2.53(t, J=4 Hz, 4H); MS [M+H]⁺=529.0; LCMS RT=2.29min.

Example 82 Preparation of tert-butyl4-[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate

The procedure used for the preparation of Example 1 was used to preparethe title compound by substituting the product of step 2 in thepreparation of Intermediate I for Intermediate C. ¹H-NMR (CH₂Cl₂-d₂) δ8.63 (dd, J=4, 2 Hz, 1H), 8.35 to 8.28 (m, 3H), 7.91 (s, 1H), 7.31 to7.16 (m, 3H), 6.70 (s, 1H), 5.67 to 5.63(broad, 2H), 4.10(s, 2H),3.47(t, J=3 Hz, 4H), 2.53(t, J=3 Hz, 4H), 1.41(s, 9H); MS [M+H]⁺=529.0;LCMS RT=2.29 min.

Example 83 Preparation ofN-[4-(4-amino-7{[4(methylsulfonyl)-piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 81 (60 mg, 0.10 mmol) in CH₂Cl₂/THF (3/1, 2 ml)was added triethylamine (0.01 ml, 0.10 mmol) and methanesulfonylchloride (0.01 ml, 0.10 mmol). The reaction was stirred at rt for 2 hand the reaction was concentrated. The resulting crude product waspurified via column chromatography (5:95, v/v, CH₂Cl₂—CH₃OH) to afford21 mg of the title compound (yield 50%). ¹H-NMR (DMSO-d₆) δ 9.29(s, 1H),8.93 (d, J=3 Hz, 1H), 8.62 (dd, J=7, 2 Hz, 1H), 7.89 (s, 1H), 7.57 (dd,J=7, 2 Hz, 2H), 7.53 to 7.46(m, 4H), 6.63(s, 1H), 3.83(s, 2H), 3.08(m,4H), 2.83(s, 3H), 2.55(m, 4H); MS [M+H]⁺=607.1; LCMS RT=2.56 min.

Example 84 Preparation ofN-[4-(4-amino-7-{[4-(ethylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 83 was used to preparethe title compound by substituting ethanesulfonyl chloride formethanesulfonyl chloride. ¹H-NMR (DMSO-d₆) δ 9.29(s, 1H), 8.93 (d, J=3Hz, 1H), 8.62 (dd, J=7, 2 Hz, 1H), 7.89 (s, 1H), 7.57 (dd, J=7, 2 Hz,2H), 7.53 to 7.46(m, 4H), 6.63(s, 1H), 3.87(s, 2H), 3.15(t, J=5 Hz, 4H),3.01 (q, J=7 Hz, 2H), 2.52(t, J=5 Hz, 4H), 1.17(t, J=7 Hz, 3H); MS[M+H]⁺=621.0; LCMS RT=2.61 min.

Example 85 Preparation ofN-[4-(4-amino-7-{[4(isopropylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 83 was used to preparethe title compound by substituting isopropylsulfonyl chloride formethanesulfonyl chloride. ¹H-NMR (CH₃OH-d₄) δ 8.60(d, J=7 Hz, 1H), 7.85(d, J=3 Hz, 1H), 7.61 to 7.58 (m, 2H), 7.47 to 7.42 (m, 2H), 7.35 to7.32 (m, 2H), 4.10(s, 2H), 3.35(t, J=5 Hz, 4H), 2.15(q, J=2 Hz), 2.63(t,J=5 Hz, 4H), 1.29(d, J=5 Hz, 6H); MS [M+H]⁺=635.0; LCMS RT=2.69 min.

Example 86 Preparation ofN-{4-[4-amino-7-({4-[(2,2,2-trifluoroethyl)sulfonyl]piperazin-1-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 83 was used to preparethe title compound by substituting 2,2,2-trifluoroethanesulfonylchloride for methanesulfonyl chloride. ¹H-NMR (DMSO-d₆) δ 9.29(s, 1H),8.93 (d, J=3 Hz, 1H), 8.62 (dd, J=7, 2 Hz, 1H), 7.89 (s, 1H), 7.57 (dd,J=7, 2 Hz, 2H), 7.50 to 7.38(m, 4H), 6.63(s, 1H), 4.57(q, J=8 Hz),3.15(br, 4H), 2.52(br, 4H); MS [M+H]⁺=675.2; LCMS RT=2.83 min.

Example 87 Preparation ofN-(4-7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 81 (40 mg, 0.08 mmol) in 2-propanol anhydrous(2 ml) was added acetyl chloride (0.02 ml, 0.22 mmol) and sodiumcarbonate (10 mg). The reaction was stirred at rt for 2 h and thesolvent was stripped by rotary evaporation and the resulting crude wasadded CH₂Cl₂ (3 ml) and washed with saturated aq. sodium carbonate anddried (Na₂SO4). After concentrated, the resulting brown solid wastriturated with CH₂Cl₂ to afford 20 mg of the title compound (yield46%). ¹H-NMR (DMSO-d₆) δ 9.29 (br, 2H), 8.62 (dd, J=7, 2 Hz, 1H), 7.89(s, 1H), 7.58(d, J=3 Hz, 2H), 7.56 to 7.34(m, 4H), 6.63(s, 1H), 3.87(s,2H), 3.40(t, J=3 Hz, 4H), 2.25(t, J=3 Hz, 4H), 1.95(s, 3H); MS[M+H]⁺=571.0; LCMS RT=2.91 min.

Example 88 Preparation ofN-(5-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}pyridin-2-yl)-N′-[2-fluoro-5(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 1 was used to preparethe title compound by substituting the product of step 2 in thepreparation of Intermediate J for Intermediate C and the appropriateboranate ureas. ¹H-NMR (DMSO-d₆) δ 10.01(s, 1H), 8.68 (m, 1H), 8.32(d,J=3 Hz, 1H), 7.98 (s, 1H), 7.91 to 7.82(m, 2H), 7.56 to 7.43 (m, 3H),6.7(s, 1H), 3.87(s, 2H), 3.42 to 3.38(m, 4H), 2.45 to 2.40 (m, 4H),1.95(s, 3H); MS [M+H]⁺=572.0; LCMS RT=2.87 min.

Example 89 Preparation ofN-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate J for Intermediate E.¹H-NMR (DMSO-d₆) δ 9.4(d, J=3 Hz, 1H), 9.24 (d, J=3 Hz, 1H), 8.64(dd,J=5, 2 Hz, 1H), 8.26 (t, J=8 Hz, 1H), 7.90 (s, 1H), 7.53 to 7.22(m, 4H),6.70(s, 1H), 3.85(s, 2H), 3.41 to 3.39(m, 4H), 2.45 to 2.40 (m, 4H),1.94(s, 3H); MS [M+H]⁺=589.0; LCMS RT=2.48 min.

Example 90 Preparation of tert-butyl4-(4-amino-5-[4-([(6-bromopyridin-2-yl)amino]carbonylamino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)piperazine-1-carboxylate

To a solution of Intermediate I (600 mg, 1.42 mmol), triethylamine (215mg, 2.12 mmol) in DMF (18 mL) was added (6-bromo-pyridin-2-yl)-carbamicacid phenyl ester (498 mg, 1.70 mmol). The reaction was stirredovernight, concentrated and purified by silica gel column using 4%methanol in dichloromethane to obtain 700 mg (79%) of desired product asyellow solid. ¹H-NMR (DMSO-d₆) δ 11.33 (s, 1H), 7.90 (s, 1H), 7.75 (d,J=8.4, 2H), 7.58 (t, J=8.4, 1H), 7.48 (d, J=8.4, 2H), 7.20 (d, J=8.4,1H), 6.89 (d, J=8.4, 1H), 6.65 (s, 1H), 3.98 (s, 2H), 3.42 (s, 4H), 2.58(s, 4H), 1.45 (s, 9H); MS [M+H]⁺=622; LCMS RT=2.67.

Example 91 Preparation ofN-4-[4-amino-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl-N′-(6-bromopyridin-2-yl)urea

To a solution of Example 90 (150 mg, 0.24 mmol) in dichloromethane (2mL) was added TFA (1 mL). The reaction was stirred 4 h and concentrated.The residue was dissolved in dichloromethane and washed with saturatedNa₂CO₃ solution (3×). The organic layer was dried over Na₂SO₄ andconcentrated to afford 100 mg (78%) of desired product as brown oil.¹H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 7.90 (s, 1H), 7.80 (d, J=8.4, 1H), 7.68(t, J=8.4, 1H), 7.59 (d, J=8.4, 2H), 7.40 (d, J=8.4, 2H) 7.21 (d, J=8.4,1H), 6.61 (s, 1H), 3.80 (s, 2H), 2.68 (t, J=2.4, 4H), 2.40 (s, 4H); MS[M+H]⁺=522; LCMS RT=1.65.

Example 92 Preparation ofN-(4-4-amino-7-[(4-isopropylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-ylphenyl)-N′-(6-bromopyridin-2-yl)urea

To a solution of Example 91 (40 mg, 0.077 mmol), Cs₂CO₃ (32 mg, 0.1mmol) in MeCN (1 mL) was added 2-iodopropane (15 mg, 0.084 mmol). Thereaction mixture was stirred at 50° C. overnight. The crude product waspurified by HPLC to afford 13 mg (30%) of desired product. ¹H-NMR(DMSO-d₆) δ 11.40 (s, 1H), 11.32 (s, 1H), 7.90-7.85 (M, 2H), 7.68 (d,J=8.4, 2H), 7.62 (t, J=8.8, 1H), 7.36 (d, J=8.4, 2H), 7.15 (d, J=8.8,1H), 6.59 (s, 1H), 3.80 (s, 2H), 2.50-2.35 (br, 9H), 0.95 (d, J=8.4,6H); MS [M+H]⁺=564; LCMS RT=2.18.

Example 93 Preparation ofN-(4-7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-ylphenyl)-N′-(6-bromopyridin-2-yl)urea

To a solution of Example 91 (40 mg, 0.077 mmol), Na₂CO₃ (11 mg, 0.1mmol) in DMF (1 mL) was added acetyl chloride (6 mg, 0.084 mmol). Thereaction mixture was stirred at rt overnight. After removal of solvent,the crude product was purified by silica gel column using 4% methanol indicliloromethane to obtain 28 mg (65%) of desired product. ¹H-NMR(DMSO-d₆) δ 9.75 (s, 1H), 9.62 (s, 1H), 7.91 (s, 1H), 7.78 (d, J=8.8,1H), 7.68 (t, J=8.8, 1H), 7.59 (d, J=8.8, 2H), 7.42 (d, J=8.8, 2H), 7.25(d, J=8.8, 1H), 6.62 (s, 1H), 3.85 (s, 2H), 2.42-2.38 (m, 8H), 1.95 (s,3H); MS [M+H]⁺=564; LCMS RT=2.20.

Example 94 Preparation ofN-[4-(4-amino-7-[4-(methylsulfonyl)piperazin-1-yl]methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea

To a solution of Example 91 (40 mg, 0.077 mmol), Na₂CO₃ (11 mg, 0.1mmol) in DMF (1 mL) was added methanesulfonyl chloride (9.6 mg, 0.084mmol). The reaction mixture was stirred at rt overnight. After removalof solvent, the crude product was purified by silica gel column using 4%methanol in dichloromethane to obtain 23 mg (50%) of desired product.¹H-NMR (DMSO-_(d)) δ 9.75 (s, 1H), 9.60 (s, 1H), 7.90 (s, 1H), 7.78 (d,J=8.4, 1H), 7.70 (t, J=8.4, 1H), 7.59 (d, J=8.4, 2H), 7.42 (d, J=8.4,2H), 7.25 (d, J=8.4, 1H), 6.63 (s, 1H), 3.87 (s, 2H), 3.10 (s, 4H), 2.83(s, 3H), 2.43 (s, 4H); MS [M+H]⁺=601; LCMS RT=2.50.

Example 95 Preparation ofN-[4-(4-amino-7-[4-(2-hydroxyethyl)piperazin-1-yl]methylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea

To a solution of Example 91 (50 mg, 0.096 mmol), Cs₂CO₃ (40 mg, 0.124mmol) in DMF (1 mL) was added (2-bromoethoxy)-t-butyldimethylsilane (25mg, 0.105 mmol). The reaction mixture was stirred at rt overnight. Afterremoval of solvent, the crude product was dissolved in methanol (1 mL)followed by adding 10% TFA in water (1 mL). The solution was stirred for3 hr at 50° C. Cooled and concentrated, the crude product was purifiedby silica gel column using 4% methanol. in dichloromethane to obtain 3mg (5%) of desired product. ¹H-NMR (DMSO-d₆) δ 10.30 (s, 2H), 7.90 (s,1H), 7.83 (d, J=8.4, 1H), 7.66 (t, J=8.4, 1H), 7.61 (d, J=8.4, 2H), 7.40(d, J=8.4, 2H), 7.21 (d, J=8.4, 1H), 6.61 (s, 1H), 3.81 (s, 1H), 3.30(t, J=8.8, 2H), 3.15 (s, 4H), 2.43 (s, 4H), 2.31 (t, J=8.8, 2H); MS[M+H]⁺=567; LCMS RT=2.29.

Example 96 Preparation of4-amino-N-(2,2,2-trifluoroethyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

Step 1: Preparation of butyl4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate

A mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (670.0 mg, 3.15mmol), palladium acetate (70.6 mg, 0.31 mmol),1,3-bis(diphenylphosphino)propane (142.7 mg, 0.35 mmol), potassiumcarbonate (652.0 mg, 4.72 mmol), and 1-butanol (4 mL) in DMF (4 mL) wasstirred under carbon monoxide at 80° C. for 4 h. The solid was filteredaway and the filtrate was purified by HPLC using a gradient of 25-50% ofMeCN in water to yield 107.3 mg (15%) of the title compound as a whitesolid. ¹H-NMR (DMSO-d₆) δ 8.28 (bs, 1H), 8.17, (bs, 1H), 8.05 (s, 1H),7.25 (d, J=4.7 Hz, 1H), 7.00 (d, J=4.6 Hz, 1H), 4.24 (t, J=6.6 Hz, 2H),1.69-1.62 (m, 2H), 1.45-1.36 (m, 2H), 0.92 (t, J=7.3, 3H); MS[M+H]⁺=235.2; LCMS RT=2.73 min.

Step 2: Preparation of butyl4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate

To a solution of butyl4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (225.0 mg, 0.96 mmol)in DMF (7.5 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (137.3 mg,0.48 mmol) in two portions. The solution was stirred for 4 days and thenquenched by addition of saturated aqueous sodium sulfate solution (20mL) and water (20 mL). The solid was filtered, washed with water andair-dried. The crude material was purified by HPLC using a gradient of30-80% of MeCN in water to afford 232.0 mg (77%) of the title compoundas an off-white solid. ¹H-NMR (DMSO-d₆) δ 8.42 (bs, 1H), 8.03 (s, 1H),7.35 (s, 1H), 7.03 (bs, 1H), 4.23 (t, J=6.4 Hz, 2H), 1.69-1.62 (m, 2H),1.46-1.36 (m, 2H), 0.92 (t, J=7.3, 3H); MS [M+H]⁺=313.0; LCMS RT=2.83min.

Step 3: Preparation of butyl4-amino-5-{4-[(tert-butoxycarbonyl)amino]phenyl}-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate

A mixture of butyl4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (456.0 mg,1.46 mmol), {4-[(tert-butoxycarbonyl)amino]phenyl}boronic acid (517.8mg, 2.18 mmol), 2 M aqueous sodium carbonate solution (2.2 mL, 4.40mmol), and tetrakis(triphenylphosphine)palladium(0) (168.3 mg, 0.15mmol) in 1,2-dimethoxyethane (11 mL) was heated (80° C.) overnight. Thereaction mixture was diluted with DMF and purified by HPLC using agradient of 30-95% of MeCN in water to give 163.2 mg (26%) of the titlecompound as a white solid. 1H-NMR (DMSO-d₆) δ 9.52 (s, 1H), 8.08 (bs,1H), 8.06 (s, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.6 Hz, 2H), 7.18(s, 1H), 5.67 (bs, 1H), 4.25 (t, J=6.5 Hz, 2H), 1.71-1.64 (m, 2H),1.47-1.37 (m, 2H), 0.93 (t, J=7.4, 3H); MS [M+H]⁺=426.2; LCMS RT=3.43min.

Step 4: Preparation of butyl4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate

To a suspension of butyl4-amino-5-{4-[(tert-butoxycarbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate(174.5 mg, 0.41 mmol) in dichloromethane (4 mL) was added TFA (2 mL).The solution was stirred at rt for 6.5 h and then the volatiles wereevaporated under reduced pressure. The residue was dissolved in ethylacetate (150 mL) and then this solution was washed with saturatedaqueous sodium bicarbonate solution and water, dried over sodiumsulfate, and concentrated to dryness under reduced pressure to afford132.7 mg (99%) of the title compound. ¹H-NMR (DMSO-d₆) δ 8.10 (bs, 1H),8.02 (s, 1H), 7.10 (d, J=8.3 Hz, 2H), 7.08 (s, 1H), 6.64 (d, J=8.4 Hz,2H), 5.55 (bs, 1H), 5.34 (s, 2H), 4.24 (t, J=6.5 Hz, 2H), 1.70-1.63 (m,2H), 1.46-1.37 (m, 2H), 0.93 (t, J=7.4, 3H); MS [M+H]⁺=326.3; LCMSRT=2.07 min.

Step 5: Preparation of butyl4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate

To a solution of butyl4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate(118.0 mg, 0.36 mmol) in DMF (3.5 mL) was addedphenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate (153.5 mg, 0.54 mmol),followed by triethylamine (0.10 mL, 0.73 mmol). The solution was stirredat rt overnight and then purified directly by HPLC using a gradient of50-80% MeCN in water to yield 107.7 mg (58%) of the title compound as awhite solid. ¹H-NMR (DMSO-d₆) δ 9.88 (s, 1H), 9.73 (s, 1H), 8.08 (s,1H), 8.04 to 7.97 (m, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.51 to 7.49 (m, 1H),7.44 (d, J=8.5 Hz, 2H), 7.22 (s, 1H), 4.26 (t, J=6.6 Hz, 2H), 1.71-1.64(m, 2H), 1.47-1.38 (m, 2H), 0.93 (t, J=7.3, 3H); MS [M+H]⁺=514.2; LCMSRT=3.49 min.

Step 6: Preparation of4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylicacid

A mixture of butyl4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate(96.0 mg, 0.19 mmol) and 1 N aqueous sodium hydroxide solution (0.94 mL,0.94 mmol) in THF (4 mL) and MeOH (5 mL) was stirred at rt for 4 h andacidified to pH 3 using 2N hydrochloric acid. The organic solvents wereevaporated under reduced pressure and the residue was suspended in water(5 mL). The solid was filtered, washed with water and air-dried to give63.0 mg (74%) of the title compound. ¹H-NMR (DMSO-d₆) δ 12.76 (s, 1H),9.87 (s, 1H), 9.71 (s, 1H), 8.08 (s, 1H), 8.04-7.97 (m, 2H), 7.57 (d,J=8.6 Hz, 2H), 7.50-7.49 (m, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.20 (s, 1H);MS [M+H⁺=458.0; LCMS RT=2.90 min.

Step 7: Preparation of Title Compound

A mixture of4-amino-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxylicacid (30.0 mg, 0.066 mmol), 2,2,2-trifluoroethylamine (32.5 mg, 0.33mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (58.0 mg, 0.13 mmol), and 4-methylmorpholine (13.3mg, 0.13 mmol) in DMF (2 mL) was stirred at rt overnight. The crudereaction mixture was purified directly by HPLC using a gradient of30-90% MeCN in water to afford 16.4 mg (36%) of the title compound as awhite solid. ¹H-NMR (DMSO-d₆) δ 9.88 (s, 1H), 9.73 (s, 1H), 9.40 (t,J=6.6 Hz, 1H), 8.34 (bs, 1H), 8.18 (s, 1H), 8.05 to 7.98 (m, 2H), 7.58(d, J=8.6. Hz, 2H), 7.51-7.49 (m, 1H), 7.44 (d, J=8.7 Hz, 2H), 7.24 (s,1H), 5.94 (bs, 1H), 4.33-4.24 (m, 2H); MS [M+H]⁺=539.0; LCMS RT=3.24min.

Example 97 Preparation of4-amino-N-(tert-butyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

The procedure used for the preparation of Example 96 was used to preparethe title compound by substituting tert-butylamine for2,2,2-trifluoroethylamine in step 7. ¹H-NMR (DMSO-d₆) δ 9.87 (s, 1H),9.72 (s, 1H), 8.97 (s, 1H), 8.21 (bs, 1H), 8.12 (s, 1H), 8.05-7.97 (m,2H), 7.57 (d, J=8.8 Hz, 2H), 7.51-7.49 (m, 1H), 7.42 (d, J=8.6 Hz, 2H),7.13 (s, 1H), 5.86 (bs, 1H), 1.44 (s, 9H); MS [M+H]⁺=513.2; LCMS RT=3.37min.

Example 98 Preparation ofN-[4-(7-acetyl-4-aminopyrrolo[2,1-f[1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of1-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanone

A mixture of Intermediate W (360.0 mg, 1.41 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (618.4 mg, 2.82mmol), tetrakis(triphenylphosphine)palladium(0) (163.1 mg, 0.14 mmol),and 2 M aqueous potassium carbonate solution (2.82 mL, 5.64 mmol) in1,2-dimethoxyethane (7 mL) was heated (80° C.) overnight. After coolingthe reaction mixture was purified directly by silica gel chromatographyusing a 1:1 mixture of ethyl acetate and hexanes to give 300.0 mg (80%)of the title compound. ¹H-NMR (DMSO-d₆) δ 9.56 (d, J=3.2 Hz, 1H), 8.21(d, J=3.0, 1H), 8.04 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.54 (s, 1H), 6.64(d, J=8.7 Hz, 2H), 5.38 (bs, 2H), 2.61 (s, 3H); MS [M+H]⁺=268.2; LCMSRT=1.79 min.

Step 2: Preparation of Title Compound

A mixture of1-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanone(50.0 mg, 0.19 mmol), phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate(105.6 mg, 0.37 mmol), and triethylamine (0.10 mL, 0.75 mmol) in DMF (2mL) was stirred overnight resulting in formation of a precipitate. Themixture was diluted with DMSO (1 mL) and then the solid was collected byfiltration, washed with MeOH, and air-dried to give 53.0 mg (62%) of thetitle compound. ¹H-NMR (DMSO-d₆) δ 9.87 (s, 1H), 9.71 (s, 1H), 9.60 (d,J=3.2 Hz, 1H), 8.34 (d, J=3.3, 1H), 8.10 (s, 1H), 8.04-8.02 (m, 4H),7.76 (s, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.52-7.50 (m, 1H), 2.64 (s, 3H);MS [M+H]⁺=456.1; LCMS RT=3.25 min.

Example 99 Preparation ofN-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea

The procedure used for the preparation of Example 98 was used to preparethe title compound by substituting phenyl (6-bromopyridin-2-yl)carbamatefor phenyl [6-(trifluoromethyl)pyridin-2-yl]carbamate in step 4. ¹H-NMR(DMSO-d₆) δ 9.63 (s, 1H), 9.60 (d, J=2.5 Hz, 1H), 9.46 (s, 1H), 8.34 (d,J=3.2, 1H), 8.10 (s, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.80 (d, J=8.2 Hz,1H), 7.74 (s, 1H), 7.71-7.67 (m, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.24 (d,J=7.6 Hz, 1H), 2.63 (s, 3H); MS [M+H]⁺=466.1; LCMS RT=3.36 min.

Example 100 Preparation ofN-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of1-[4-amino-5-(4aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]ethanone(50.0 mg, 0.19 mmol) and 2-fluoro-5-trifluoromethyl isocyanate (76.7 mg,0.37 mmol) in 1,2-dichloroethane (2 mL) was heated (80° C.) overnight.After cooling, DMF (2 mL) and 2 N hydrochloric acid (0.1 mL) were addedand the resulting solution was heated (80° C.) overnight.1,2-Dichloroethane was evaporated under reduced pressure and the residuewas suspended in MeOH (10 mL). The product was filtered and air-dried togive 65.2 mg (74%) of the title compound. ¹H-NMR (DMSO-d₆) δ 9.60 (d,J=3.5 Hz, 1H), 9.37 (s, 1H), 8.95 (d, J=2.9, 1H), 8.64-8.62 (m, 1H),8.34 (d, J=3.42 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.75 (s,1H), 7.59 (d, J=8.7 Hz, 2H), 7.53-7.48 (m, 1H), 7.41-7.38 (m, 1H), 2.64(s, 3H); MS [M+H]⁺=473.2; LCMS RT=3.35 min.

Example 101 Preparation ofN-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-trifluoromethyl)pyridin-2-yl]urea

To a suspension of Example 98 (74.8 mg, 1.98 mmol) in MeOH (6 mL) wasadded NaBH₄ (24.9 mg, 0.66 mmol). The mixture was stirred at rt for 2 d.and then diluted with DMF (3 mL). This solution was purified directly byHPLC using a gradient of 15-90% MeCN in water to afford 14.4 mg (48%) ofthe title compound. ¹H-NMR (DMSO-d₆) δ 9.87 (bs, 1H), 9.71 (bs, 1H),8.04-7.98 (m, 5H), 7.56 (d, J=9.1 Hz, 2H), 7.52-7.50 (m, 1H), 7.03 (s,1H), 6.68 (bs, 2H), 5.11 (q, J=6.4 Hz, 1H), 1.74 (s, 1H), 1.47 (d, J=6.7Hz, 3H); MS [M+H]⁺=458.1; LCMS RT=2.76 min.

Example 102 Preparation ofN-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea

The procedure used for the preparation of Example 101 was used toprepare the title compound by substituting Example 99 for Example 98.¹H-NMR (DMSO-d₆) δ 9.63 (bs, 1H), 9.47 (bs, 1H), 8.02 (s, 1H), 7.98 (d,J=8.8 Hz, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.71-7.68 (m, 1H), 7.56 (d, J=8.8Hz, 2H), 7.24 (d, J=7.4 Hz, 1H), 7.02 (s, 1H), 6.68 (bs, 2H), 5.11 (q,J=6.0 Hz, 1H), 1.74 (s, 1H), 1.47 (d, J=6.7 Hz, 3H); MS [M+H]⁺=468.0;LCMS RT=2.72 min.

Example 103 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylacetyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

Step 1: Preparation ofN-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation ofN-[4-(7-bromoacetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Example 100 in THF (5 mL) was cooled to −78° C. andtreated with diisopropylethyl amine (0.424 mL, 2.57 mmol) followed bytrimethylsilyltriflate (0.421 mL, 2.177 mmol). The reaction was allowedto warm to rt over 30 min, then cooled again to −78° C. and treated with1,3-dibromo-5,5-dimethylhydantoin (62 mg, 0.218 mmol). The reaction wasallowed to stir for 1 h at −78 C, then warmed to rt and quenched withmethanol (200 uL) and diluted with ethyl acetate and 1N sodium sulfitesolution. The organic layer was separated, washed with 1 N bisulfatebuffer (pH 2), dried with sodium sulfate and passed thru a silica plug.Evaporation of the solvent gave a yellow solid which was triturated withEt₂O:hexanes (1:1) to provide the title compound as a yellow solid (154mg, 70% Yield). ¹H-NMR (DMSO-d₆) δ 9.18 (s, 1H), 8.45 to 8.48 (m, 1H),8.02 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.27 (s,1H), 7.20 to 7.37 (m, 4H), 4.77 (s, 2H). MS [M+H]⁺=551.2; LCMS RT=3.63.

Step 2: Preparation of Title Compound

A solution ofN-[4-(7-bromoacetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea(65 mg, 0.12 mmol) in 2 mL THF was treated with morpholine (53 uL, 0.59mmol) and allowed to stir for 15 min. The reaction was then diluted with50 mL EtOAc and 5 mL toluene & washed with sodium carbonate solution(1×). The organic layer dried with sodium sulfate and concentrated togive a yellow oil. Trituration with Et₂O:hexanes (1:1) gave the titlecompound as a faintly yellow powder (52.4 mg, 79% Yield). ¹H-NMR(DMSO-d₆) δ 9.28 (s, 1H), 8.84 (s, 1H), 8.43 to 8.47 (m, 1H). 7.95 (s,1H), 7.42 (d, J=8.7 Hz, 2H), 7.19 to 7.31 (m, 3H) 7.25 (d, J=8.7 Hz,2H), 7.17 (s, 1H), 3.76 (s, 2H), 3.38 to 3.43 (m, 4H), 2.35 to 2.41 (m,4H); MS [M+H]⁺=557.9; LCMS RT=2.57.

Example 104 Preparation ofN-{4-[4-amino-7-(1-hydroxy-1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of the product of step 1 of Example 103 (48 mg, 0.10 mmol)in 2 mL THF was treated with methylmagnesium bromide (3N solution inEt₂O, 339 uL, 1 mmol) at rt. After stirring for 15 min at rt thereaction appeared complete by TLC (EtOAc). The reaction was quenchedwith 200 uL MeOH and diluted with 100 mL EtOAc and 100 mL 1N NaH₂PO₄solution. The organic layer was dried (Na₂SO₄) and filtered through asilica plug before concentrating to a white solid (42.2 mg, 85% Yield).¹H-NMR (DMSO-d₆) δ 9.51 (s, 1H), 9.04 (bs, 1H), 8.62 (dd, J=7.2, 2 Hz,1H), 7.88 (s, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.44 to 7.53 (m, 1H), 7.39(m, 1H), 7.37 (d, J=8.7 Hz, 2H), 7.13 (bs, 1H), 6.57 (s, 1H), 5.31 (s,1H), 1.60 (s, 6H); MS [M+H]⁺=489.2; LCMS RT=3.01.

Example 105 Preparation ofN-{4-[4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol

To a cooled (0° C.) solution of the product of step 4 of Example 96(220.0 mg, 0.68 mmol) in THF (23 mL) was added diisobutylaluminumhydride (1 M in THF, 7.4 mL, 7.4 mmol). The mixture was allowed to warmto rt and stirred for 30 min. The reaction was cooled (0° C.) andquenched with methanol (1 mL). The mixture was poured into a vigorouslystirred 1.2 M aqueous Rochelle's salt solution (50 mL). The resultantmixture was stirred for 30 min and then extracted with ethyl acetate(3×50 mL). The combined organic extracts were dried over sodium sulfateand concentrated to dryness under reduced pressure. The crude materialwas purified by HPLC using a gradient of 50-90% MeCN in water to yield170.0 mg (99%) of the desired product containing trace impurities.¹H-NMR (DMSO-d₆) δ 8.14 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.0Hz, 2H), 6.76 (s, 1H), 4.75 (s, 2H); MS [M+H]⁺=256.2; LCMS RT=1.05 min.

Step 2: Preparation of Title Compound

A solution of[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]methanol(170.0 mg, 0.67 mmol), phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate(281.9 mg, 1.00 mmol), and triethylamine (0.46 mL, 1.33 mmol) in DMF (5mL) was stirred at rt for 3 d. The crude reaction mixture was purifieddirectly by HPLC using a gradient of 20-90% MeCN in water to yield 21.1mg (7%) of the title compound. ¹H-NMR (DMSO-d₆) δ 9.89 (bs, 1H), 9.72(bs, 1H), 8.05-7.98 (m, 2H), 7.89 (s, 1H), 7.57 (d, J=8.6 Hz, 2H),7.51-7.49 (m, 1H), 7.40 (d, J=8.6 Hz, 1H), 6.64 (s, 1H), 5.19 (t, J=5.7Hz, 1H), 4.74 (d, J=5.6 Hz, 3H); MS [M+H]⁺=444.1; LCMS RT=2.63 min.

Example 106 Preparation ofN-[4-(4-amino-7-{[(2,2,2-trifluoroethyl)amino]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation ofN-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea

To a suspension of Example 105 (14.7 mg, 0.033 mmol) in THF (3 mL) wasadded 3,3,3-triacetoxy-3-iodophthalide (42.2 mg, 0.10 mmol). The mixturewas stirred at rt under nitrogen for 4 d. The solvent was evaporatedunder reduced pressure. The residue was dissolved in DMF and purified byHPLC using a gradient of 20-90% MeCN in water to yield 6.0 mg (41%) ofthe title compound. ¹H-NMR (DMSO-d₆) δ 10.34 (s, 1H), 9.90 (bs, 1H),9.75 (bs, 1H), 8.15 (s, 1H), 8.06-7.99 (m, 2H), 7.59 (d, J=8.6, 2H),7.51 (dd, J=7.0, 1.1, Hz, 1H), 7.46 (d, J=8.5 Hz, 2H), 7.25 (s, 1H); MS[M+H]⁺=442.1; LCMS RT=3.29 min.

Step 2: Preparation of Title Compound

To a suspension ofN-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea(5.0 mg, 0.011 mmol) in 1,2-dichloroethane (2 mL) was added2,2,2-trifluoroethylamine (11.2 mg, 0.11 mmol), followed by sodiumtriacetoxyborohydride (24.0 mg, 0.11 mg). The mixture was stirred at rtunder nitrogen for 4 d. The solvent was evaporated under reducedpressure. The residue was dissolved in DMF and purified by HPLC using agradient of 20-90% MeCN in water to yield 2.1 mg (35%) of the titlecompound. ¹H-NMR (DMSO-d₆) δ 9.95 (bs, 1H), 9.79 (bs, 1H), 8.05-7.99 (m,2H), 7.90 (s, 1H), 7.57 (d, J=8.6, 2H), 7.50 (dd, J=6.4, 1.7, Hz, 1H),7.40 (d, J=8.6 Hz, 2H), 6.66 (s, 1H), 4.07 (d, J=6.8 Hz, 2H), 3.30-3.23(m, 2H), 2.92-2.85 (m, 1H); MS [M+H]⁺=525.1; LCMS RT=2.91 min.

Example 107 Preparation ofN-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate X for Intermediate E andsubstituting Intermediate H forphenyl(3-tert-butylisoxazol-5-yl)carbamate. ¹H-NMR (DMSO-d₆) δ 9.84(s,1H), 9.72(s, 1H), 8.52 (d, J=6 Hz, 1H), 8.05(s, 1H), 7.86(s, 1H), 7.61to 7.59 (m, 2H), 7.40 to 7.34(m, 3H), 6.52(s, 1H), 3.57 to 3.52 (m, 4H),2.87(t, J=7 Hz, 2H), 2.35 to 2.24(m, 6H), 1.83(t, J=7 Hz, 2H); MS[M+H]⁺=541.2; LCMS RT=2.44 min

Example 108 Preparation ofN-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A mixture of Intermediate V (70 mg, 0.20 mmol), Intermediate M (130 mg,0.30 mmol), Na₂CO₃ (44 mg, 0.40 mmol),tetrakis-(triphenylphosphine)palladium (24 mg, 0.02 mmol), toluene (3.5ml) and H₂O (0.45 ml) was degassed and filled with N₂ and was heated at80 C under N₂ for 16 h. After cooled to rt, the reaction mixture wasadded ethyl acetate and washed with aq. saturated NaHCO₃ and dried overNa₂SO₄. The crude was concentrated and purified via columnchromatography (95:5 v/v CH₂Cl₂—CH₃OH) to afford 17 mg of the titlecompound (yield 15%). ¹H-NMR (DMSO-d₆) δ 9.28 (s, 1H), 8.93(d, J=3 Hz,1H), 8.62 (dd, J=8, 3 Hz, 1H), 7.86(s, 1H), 7.57 to 7.35(m, 6H), 6.52(s,1H), 3.53 (t, J=4 Hz, 4H), 2.87(t, J=7 Hz, 2H), 2.35 to 2.24(m, 6H),1.85 to 1.80(m, 2H); MS [M+H]⁺=558.2; LCMS RT=2.62 min

Example 109 Preparation ofN-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting Intermediate O forIntermediate M. ¹H-NMR (DMSO-d₆) δ 9.39 (d, J=3 Hz, 1H), 9.24 (d, J=3Hz, 1H), 8.65(dd, J=7, 3 Hz, 1H), 8.24(t, J=7 Hz, 1H), 7.87(s, 1H),7.53(t, J=8 Hz, 1H), 7.41 to 7.38(m, 1H), 7.32 to 7.19(m, 2H), 6.56(s,1H), 3.53 (t, J=4 Hz, 4H), 2.87(t, J=4 Hz, 2H), 2.35 to 2.24(m, 6H),1.85 to 1.80(m, 2H); MS [M+H]⁺=576.2; LCMS RT=2.92 min.

Example 110 Preparation of tert-butyl4-(4-amino-5-3-fluoro-4-[([2-fluoro-5-(trifluoromethyl)phenyl]aminocarbonyl)amino]phenylpyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a flask charged with N₂ was added Intermediate AC (1.29 g, 3.26 mmol)and Intermediate O (1.44 g, 3.26 mmol) followed by 1,4-dioxane (31 mL).N₂ was bubbled through the solution for 15 min and thendichlorobis(triphenylphosphine)palladium(II) (229 mg, 0.326 mmol) wasadded followed by aq 1M Na₂CO₃ (6.51 mL, 6.51 mmol). N₂ was bubbledthrough the solution for an additional 15 min and, then the reaction washeated to 80° C. for 17 h. The reaction material was allowed to cool tort and was diluted with EtOAc and water. The solution was separated andthe aqueous layer was back extracted with EtOAc. The organic fractionswere combined, dried (MgSO₄), filtered, condensed, and purified by flashcolumn chromatography (9:1 CH₂Cl₂/MeOH). The material was furtherpurified by flash chromatography (50:47:3 CH₂Cl₂/EtOAc/MeOH). Thepurified fractions were collected, evaporated, and left under vacuumovernight to yield 942 mg (46%) of the desired product. ¹H-NMR (DMSO-d₆)δ 9.43 (s, 1H), 9.27 (s, 1H), 8.67 (d, J=7.5 Hz, 1H), 8.28 (t, J=8.5 Hz,1H), 7.92 (s, 1H), 7.53 (t, J=9.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.34 (d,J=10.5 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 6.62 (s, 1H), 4.08 (d, J=11.2Hz, 2H), 3.34-3.29 (m, 1H), 2.97-2.82 (br s, 2H), 2.00 (d, J=7.4 Hz,2H), 1.60-1.51 (m, 2H), 1.42 (s, 9H); MS [M+H]⁺=632; LCMS RT=3.42.

Example 111 Preparation ofN-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]-triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 110 (40 mg, 0.063 mmol) in CH₂Cl₂ (1.5 mL) wasadded trifluoroacetic acid (0.15 mL). The solution was stirred at rt for2 h and was then treated with aq NaHCO₃, EtOAc, and separated washingwith water. The product was purified by prep HPLC (1:9 ACN/H₂O rampingto 9:1 ACN/H₂O with 0.1% TFA). The resulting fractions were combined andtreated with aq NaHCO₃, EtOAc, and separated. The organic was washedwith water, collected, dried (Na₂SO₄), filtered, and evaporated todryness yielding 29 mg (86%) of the desired product as a white solid.¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=7.6 Hz, 1H),8.25 (t, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.51 (t, J=9.6 Hz, 1H), 7.41-7.38(m, 1H), 7.32 (d, J=12.3 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 6.53 (s, 1H),3.23-3.15 (m, 1H), 3.02 (d, J=12.1 Hz, 2H), 2.63 (t, J=12.0 Hz, 2H),1.92 (d, J=13.7 Hz, 2H), 1.54 (d, J=12.2 Hz, 2H); MS [M+H]⁺=532; LCMSRT=2.38.

Example 112 Preparation ofN-(4-4-amino-7-[1-(trifluoroacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of Example 111 (90 mg, 0.17 mmol) in THF (1.7 mL) wasadded trifluoroacetic anhydride (48 μL, 0.34 mmol). The solution washeated to 60° C. for 2 h. The cooled reaction material was diluted withEtOAc, aq 1N NaOH, and separated. The organic layer was washed withwater and the organic was collected, dried (Na₂SO₄), filtered, andevaporated. The material was purified by flash chromatography (9:1CH₂Cl₂/MeOH) producing 66 mg (62%) of the title compound. ¹H-NMR(DMSO-d₆) δ 9.41 (s, 1H), 9.26 (s, 1H), 8.65 (d, J=8.9 Hz, 1H), 8.26 (t,J=8.7 Hz, 1H), 7.91 (s, 1H), 7.51 (t, J=9.8 Hz, 1H), 7.43-7.39 (m, 1H),7.32 (d, J=14.1 Hz, 1H), 7.23 (d, J=8.9 Hz, 1H), 6.63 (s, 1H), 4.40 (d,J=11.4 Hz, 1H), 3.96 (d, J=14.9 Hz, 1H), 3.55-3.44 (m, 2H), 3.12-3.05(m, 1H), 2.17-2.10 (m, 2H), 1.70-1.64 (m, 2H); MS [M+H]⁺=628; LCMSRT=3.39.

Example 113 Preparation ofN-4-[4-amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 111 (40 mg, 0.075 mmol) in THF (1.0 mL) wasadded 37% formaldehyde in water (6 μL, 0.075 mmol) followed by AcOH (6μL, 0.11 mmol). The solution was stirred at rt for 1 h and then sodiumtriacetoxyborohydride (32 mg, 0.15 mmol) was added. The reaction wasallowed to stir for an additional 1 h. The reaction mixture was dilutedwith aq NaHCO₃ and EtOAc and was transferred to a separatory funnel,separated, washed with water, dried, (Na₂SO₄), filtered and evaporatedunder reduced pressure. The material was purified by flashchromatography (85:15 CH₂Cl₂/MeOH with 1% ammonium hydroxide). Theresulting purified fractions were combined and evaporated, diluted withaq NaHCO₃ and EtOAc, transferred to a separatory funnel, separated,washed with water, dried, (Na₂SO₄), filtered and evaporated to yield 26mg (63%) of the title compound as a white solid. ¹H-NMR (DMSO-d₆) δ 9.41(s, 1H), 9.24 (s, 1H), 8.65 (d, J=9.0 Hz, 1H), 8.25 (t, J=8.5 Hz, 1H),7.88 (s, 1H), 7.51 (t, J=8.7 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (d, J=12.1Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 6.55 (s, 1H), 3.06-3.00 (m, 1H), 2.85(d, J=11.0 Hz, 2H), 2.18 (s, 3H), 2.02-1.93 (m, 2H), 1.72-1.63 (m, 2H);MS [M+H]⁺=546; LCMS RT=2.39.

Example 114 Preparation ofN-4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a solution of Example 111 (50 mg, 0.094 mmol ) in DMF (1.0 mL) wasadded glycolic acid (7 mg, 0.094 mmol), andbenzotriazolyloxytris(dimethylamino)phosphonium PF₆ (42 mg, 0.094 mmol)followed by 4-methylmorpholine (10 μL, 0.094 mmol). The solution wasstirred at rt for 17 h, then evaporated under reduced pressure, andpurified by flash chromatography (9:1 CH₂Cl₂/MeOH). The purifiedfractions were combined and triturated with CH₂Cl₂/Et₂O yielding 55 mg(99%) of desired compound. ¹H-NMR (DMSO-d₆) δ 9.42 (s, 1H), 9.25 (s,1H), 8.65 (d, J=7.6 Hz, 1H), 8.26 (t, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.51(t, J=10.1 Hz, 1H), 7.42-7.38 (m, 1H), 7.31 (d, J=12.1 Hz, 1H), 7.22 (d,J=9.8 Hz, 1H), 6.57 (s, 1H), 4.53-4.45 (m, 2H), 4.12-4.09 (m, 2H), 3.78(d, J=11.4 Hz, 1H), 3.14 (t, J=11.5 Hz, 1H), 2.78 (t, J=12.3 Hz, 1H),2.02 (d, J=12.3 Hz, 2H), 1.68-1.49 (m, 2H); MS [M+H]⁺=590; LCMS RT=2.88.

Example 115 Preparation ofN-(4-4-amino-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of Example 114 (20 mg, 0.034 mmol) in THF (2 mL) was added2M SOCl₂ in CH₂Cl₂ (0.17 mL, 0.34 mmol). The solution was allowed tostir at rt for 15 min and was then evaporated under reduced pressurechasing with CH₂Cl₂. THF (4 mL) was added to the crude reaction mixturefollowed by morpholine (30 μL, 0.34 mmol) and the reaction was heated to60° C. for 6 h. The reaction mixture was allowed to cool, wasevaporated, and then purified by flash chromatography (5:4:1CH₂Cl₂/EtOAc/MeOH). The resulting fractions, upon evaporation, yielded19 mg (85%) of the desired compound as a yellow solid. ¹H-NMR (DMSO-d₆)δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=6.7 Hz, 1H), 8.25 (t, J=8.6 Hz,1H), 7.89 (s, 1H), 7.51 (t, J=9.7 Hz, 1H), 7.42-7.38 (m, 1H), 7.32 (d,J=12.1 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.56 (s, 1H), 4.46 (d, J=13.2Hz, 1H), 4.16 (d, J=13.1 Hz, 1H), 3.58-3.53 (m, 4H), 3.42-3.35 (m, 1H),3.26 (d, J=14.7 Hz, 1H), 3.18-3.12 (m, 1H), 3.05 (d, J=13.1 Hz, 1H),2.73-2.67 (m, 1H), 2.42-2.38 (m, 4H), 2.06-1.98 (m, 2H), 1.73-1.63 (m,1H), 1.52-1.45 (m, 1H); MS [M+H]⁺=659; LCMS RT=2.57.

Example 116 Preparation ofN-(4-4-amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Example 114 (27 mg, 0.046 mmol) in THF (2.5 mL) wassonicated for 10 min and then treated with 1 M diisobutylaluminumhydride in THF (0.92 mL, 0.92 mmol). The solution was stirred at rt for1 h. The r×n mixture was treated with EtOAc followed by aq Rochelle'ssalt. This heterogeneous mixture was then heated at 60° C. for 30 min.The solution was transferred to a separatory funnel, separated andwashed with water. The aq layer was back extracted with EtOAc. Theorganic solution was dried (Na₂SO₄), filtered, evaporated, and purifiedby prep HPLC (1:9 ACN/H₂O ramping to 9:1 ACN/H₂O with 0.1% TFA). Thepurified fractions were diluted in EtOAc washed with 1N NaOH, aqsaturated NaHCO₃, and water, and then dried (Na₂SO₄), filtered andevaporated under reduced pressure yielding 19 mg (72%) of desiredproduct as a white solid. ¹H-NMR (DMSO-d₆) δ 9.42 (s, 1H), 9.26 (s, 1H),8.66 (d, J=7.1 Hz, 1H), 8.26 (t, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.54-7.49(m, 1H), 7.42-7.39 (m, 1H), 7.32 (d, J=11.8 Hz, 1H), 7.23 (d, J=7.9 Hz,1H), 6.56 (s, 1H), 4.38 (t, J=5.1 Hz, 1H), 3.52-3.48 (m, 2H), 3.10-3.02(m, 1H), 2.98-2.95 (m, 2H), 2.40 (t, J=6.4 Hz, 2H), 2.11-2.05 (m, 2H),1.98-1.92 (m, 2H), 1.73-1.63 (m, 2H); MS [M+H]⁺=576; LCMS RT=2.38.

Example 117 Preparation ofN-4-[7-(1-allylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Example 111 (100 mg, 0.19 mmol) in THF (4 mL) wassonicated for 5 min and then treated with K₂CO₃ (36 mg, 0.26 mmol)followed by allyl bromide (23 μL, 0.26 mmol). The solution was heated at60° C. for 5 h. The reaction material was diluted with EtOAc and washedwith water, dried (Na₂SO₄), filtered, evaporated yielding 99 mg (92%) ofthe desired product as a white solid. ¹H-NMR (CD₃OD) δ 8.64 (d, J=7.9Hz, 1H), 8.25 (t, J=8.6 Hz, 1H), 7.82 (s, 1H), 7.36-7.33 (m, 2H),7.30-7.25 (m, 2H), 6.58 (s, 1H), 6.01-5.91 (m, 1H), 5.43-5.36 (m, 2H),3.37 (d, J=7.0 Hz, 2H), 3.34-3.29 (m, 2H), 2.58 (t, J=11.6 Hz, 2H), 2.25(d, J=13.5 Hz, 2H), 1.97-1.88 (m, 3H); MS [M+H]⁺=572; LCMS RT=2.48.

Example 118 Preparation ofethyl[4-(4-amino-5-3-fluoro-4-[([2-fluoro-5-(trifluoromethyl)phenyl]aminocarbonyl)amino]phenylpyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]acetate

A suspension of Example 111 (100 mg, 0.19 mmol) in THF (2 mL) wassonicated for 5 min and then treated with K₂CO₃ (29 mg, 0.21 mmol)followed by ethyl chloroacetate (22 μL, 0.21 mmol). The solution washeated at 60° C. for 23 h. The reaction material was diluted with EtOAcand washed with water. The aqueous layer was back extracted with EtOActwice, and the combined organic fractions were dried (Na₂SO₄), filtered,and evaporated. The crude material was purified first by flashchromatography (50:45:5 CH₂Cl₂/EtOAc/MeOH) and finally by prep HPLC (1:9ACN/H₂O ramping to 9:1 ACN/H₂O with 0.1% TFA. The resulting purifiedfractions were taken into EtOAc, washed with aq 1N NaOH, aq saturatedNaHCO₃, and water, and then dried (Na₂SO₄), filtered and reducedyielding 95 mg (82%) of the title compound as a white solid. ¹H-NMR(DMSO-d₆) 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (d, J=6.8 Hz, 1H), 8.26 (t,J=8.6 Hz, 1H), 7.88 (s, 1H), 7.53-7.48 (m, 1H), 7.42-7.38 (m, 1H), 7.32(d, J=12.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.58 (s, 1H), 4.08 (q, J=7.1Hz, 2H), 3.23 (s, 2H), 3.10-3.02 (m, 1H), 2.93 (d, J=10.0 Hz, 2H),2.34-2.29 (m, 2H), 1.96 (d, J=12.1 Hz, 2H), 1.75-1.65 (m, 2H), 1.19 (t,J=7.0 Hz, 3H); MS [M+H]⁺=618; LCMS RT=2.59.

Example 119 Preparation of[4-(4-amino-5-3-fluoro-4-[([2-fluoro-5-(trifluoromethyl)-phenyl]aminocarbonyl)amino]phenylpyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]aceticacid

To a solution of THF (5 mL) was added MeOH (2.5 mL) followed by Example118 (57 mg, 0.093 mmol) and aq 1N NaOH (0.93 mL, 0.93 mmol). Thesolution was stirred at 60° C. for 1 h and then aq 1N HCl (0.93 mL, 0.93mmol) was added. The solution was slowly reduced by rotary evaporationas a white precipitate formed which was filtered and washed with water.The solid was collected and dried under vacuum yielding 49 mg (90%) ofthe desired compound. ¹H-NMR (DMSO-d₆) δ 9.43 (s, 1H), 9.28 (s, 1H),8.65 (d, J=7.2 Hz, 1H), 8.27 (t, J=8.6 Hz, 1H), 7.91 (s, 1H), 7.54-7.49(m, 1H), 7.43-7.39 (m, 1H), 7.33 (d, J=12.4 Hz, 1H), 7.24 (d, J=7.8 Hz,1H), 6.60 (s, 1H), 3.59 (s, 2H), 3.39-3.35 (m, 2H), 3.30-3.24 (m, 2H),2.92-2.86 (m, 2H), 2.15-2.10 (m, 2H), 1.96-1.88 (m, 2H); MS [M+H]⁺=590;LCMS RT=2.49.

Example 120 Preparation of2-[4-(4-amino-5-3-fluoro-4-[([2-fluoro-5-(trifluoromethyl)phenyl]aminocarbonyl)amino]phenylpyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]-N-methylacetamide

The procedure used for the preparation of Example 114 was used toprepare the title compound by substituting methyl amine for Example 111and Example 119 for glycolic acid. ¹H-NMR (DMSO-d₆) δ 9.43 (s, 1H), 9.27(s, 1H), 8.66 (d, J=7.4 Hz, 1H), 8.26 (t, J=8.6 Hz, 1H), 7.89 (s, 1H),7.71-7.67 (m, 1H), 7.54-7.49 (m, 1H), 7.43-7.39 (m, 1H), 7.32 (d, J=12.2Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 6.55 (s, 1H), 3.10-3.04 (m, 1H), 2.91(s, 2H), 2.87 (d, J=6.4 Hz, 2H), 2.61 (d, J=4.7 Hz, 3H), 2.22-2.17 (m,2H), 1.97 (d, J=11.6 Hz, 2H), 1.82-1.76 (m, 2H); MS [M+H]⁺=603; LCMSRT=2.47.

Example 121 Preparation ofN-(4-4-amino-7-[1-(2,3-dihydroxypropyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

To a solution of Example 117 (80 mg, 0.14 mmol) in THF (2 mL) was addedwater (1 mL) 2.5% osmium tetroxide in isopropanol (0.14 mL, 0.014 mmol),and N-methylmorpholine N-oxide (25 mg, 0.21 mmol). The solution wasstirred at rt for 17 h and then treated with aq saturated Na₂SO₃ in aqsaturated NaHCO₃ (1:1) and EtOAc. The reaction mixture was allowed tostir for 1 h and then was separated washing with aq saturated Na₂CO₃ andwater. The water layer was back extracted with EtOAc (3×). The combinedorganic fractions were dried Na₂SO₄, filtered, evaporated, andtriturated in MeOH. The solid was collected and washed with ether. Themother liquor was evaporated and purified by prep HPLC (1:9 ACN/H₂Oramping to 9:1 ACN/H₂O with 0.1% TFA). The resulting purified fractionswere taken into EtOAc, washed with aq Na₂CO₃, and water, dried (Na₂SO₄),filtered, evaporated, and dried under vacuum yielding a combined 58 mg(68%) of the title compound. ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.25 (s,1H), 8.65 (d, J=7.3 Hz, 1H), 8.25 (t, J=8.6 Hz, 1H), 7.83 (s, 1H),7.53-7.48 (m, 1H), 7.42-7.38 (m, 1H), 7.32 (d, J=12.2 Hz, 1H), 7.23 (d,J=8.9 Hz, 1H), 6.56 (s, 1H), 4.61-4.52 (br s, 1H), 4.39 (s, 1H),3.64-3.58 (m, 1H), 3.10-2.94 (m, 3H), 2.42-2.36 (m, 1H), 2.32-2.24 (m,1H), 2.14-2.06 (m, 2H), 1.98-1.93 (m, 2H), 1.72-1.63 (m, 2H); MS[M+H]⁺=606; LCMS RT=2.36.

Example 122 Preparation ofN-(4-4-amino-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 116 was used toprepare the title compound by substituting Example 112 for Example 114.¹H-NMR (CD₂Cl₂) δ 8.58 (d, J=7.3 Hz, 1H), 8.24 (t, J=8.4 Hz, 1H), 7.90(s, 1H), 7.59 (s, 1H), 7.50 (s, 1H), 7.32-7.19 (m, 4H), 6.49 (s, 1H),5.52 (s, 2H), 3.24-3.17 (m, 1H), 3.09-2.99 (m, 2H), 2.54 (t, J=11.6 Hz,2H), 2.08 (d, J=11.6 Hz, 2H), 1.85-1.76 (m, 2H); MS [M+H]⁺=614; LCMSRT=3.15.

Example 123 Preparation of4-4-amino-5-[3-fluoro-4-([4-(trifluoromethyl)pyridin-2-yl]carbamoylamino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl-N-ethylpiperidine-1-carboxamide

To a solution of DCE (1.5 mL) was added Example 271 (40 mg, 0.078 mmol)and ethyl isocyanate (6 μL, 0.078 mmol). The solution was stirred at rtfor 17 h. A solid precipitate formed which was filtered and washed withCH₂Cl₂ yielding 37 mg (81%) of the desired compound. ¹H-NMR (DMSO-d₆) δ10.13 (s, 1H), 10.06-10.04 (br s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.25 (t,J=8.5 Hz, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.38 (d, J=5.4 Hz, 1H), 7.34(d, J=12.2 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 6.58 (s, 1H), 6.47 (t, J=5.4Hz, 1H), 4.06 (d, J=12.3 Hz, 2H), 3.29-3.23 (m, 1H), 3.07-3.00 (m, 2H),2.78 (t, J=12.2 Hz, 2H), 1.94 (d, J=13.2 Hz, 2H), 1.57-1.47 (m, 2H),0.99 (t, J=7.2 Hz, 3H); MS [M+H]⁺=586; LCMS RT=2.85.

Example 124 Preparation of4-4-amino-5-[3-fluoro-4-([4-(trifluoromethyl)pyridin-2-yl]carbamoylamino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl-N-tert-butylpiperidine-1-carboxamide

The procedure used for the preparation of Example 123 was used toprepare the title compound by substituting tert-butyl isocyanate forethyl isocyanate. ¹H-NMR (DMSO-d₆) δ 10.12 (s, 1H), 10.07-10.03 (br s,1H), 8.54 (d, J=5.2 Hz, 1H), 8.26 (t, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.89(s, 1H), 7.38 (d, J=5.4 Hz, 1H), 7.35 (d, J=11.8 Hz, 1H), 7.24 (d, J=8.1Hz, 1H), 6.57 (s, 1H), 5.77 (s, 1H), 4.06 (d, J=12.8 Hz, 2H), 3.25-3.22(m, 1H), 2.73 (t, J=11.8 Hz, 2H), 1.94 (d, J=13.3 Hz, 2H), 1.58-1.49 (m,2H), 1.24 (s, 9H); MS [M+H]⁺=614; LCMS RT=3.09.

Example 125 Preparation of4-4-amino-5-[3-fluoro-4-([4-(trifluoromethyl)pyridin-2-yl]carbamoylamino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl-N-isopropylpiperidine-1-carboxamide

The procedure used for the preparation of Example 123 was used toprepare the title compound by substituting iso-propyl isocyanate forethyl isocyanate. ¹H-NMR (DMSO-d₆) δ 10.13 (s, 1H), 10.08-10.02 (br s,1H), 8.54 (d, J=4.7 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.90(s, 1H), 7.38 (d, J=5.6 Hz, 1H), 7.34 (d, J=12.1 Hz, 1H), 7.24 (d, J=8.1Hz, 1H), 6.58 (s, 1H), 6.16 (d, J=7.7 Hz, 1H), 4.08 (d, J=14.6 Hz, 2H),3.77-3.72 (m, 1H), 3.28-3.22 (m, 1H), 2.76 (t, J=11.9 Hz, 2H), 1.94 (d,J9.7 Hz, 2H), 1.57-1.47 (m, 2H), 1.04 (d, J=6.7 Hz, 6H); MS [M+H]⁺=600;LCMS RT=2.84.

Example 126 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E and1-isocyanato-3-(trifluoromethyl)benzene for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.84 (s,1H), 8.52 (s, 1H), 8.30 (d, J=8.7 Hz, 1H), 8.10 (s, 1H), 7.96 (s, 1H),7.61-7.57 (m, 3H), 7.46-7.38 (m, 2H), 6.73 (s, 1H), 3.86 (s, 2H),3.61-3.58 (m, 4H), 2.50-2.48 (m, 4H); MS [M+H]⁺=546; LCMS RT=2.68.

Example 127 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(4-tert-butylpyridin-2-yl)urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate Y for Intermediate E andphenyl [4-(trifluoromethyl)pyridin-2-yl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)-carbamate. ¹H-NMR (DMSO-d₆) δ12.20-12.06 (br s, 1H), 9.93 (s, 1H), 8.43 (d, J=8.6 Hz, 1H), 8.21 (d,J=5.9 Hz, 1H), 7.91 (s, 1H), 7.55 (s, 1H), 7.38 d, J=8.6 Hz, 1H), 7.22(s, 1H), 7.09 d, J=5.8 Hz, 1H), 6.68 (s, 1H), 3.81 (s, 2H), 3.57-3.52(m, 4H), 2.46-2.41 (m, 4H), 1.25 (s, 9H); MS [M+H]⁺=547; LCMS RT=2.47.

Example 128 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E.¹H-NMR (DMSO-d₆) δ 9.73 (s, 1H), 9.01 (s, 1H), 8.65 (d, J=7.1 Hz, 1H),8.24 (d, J=8.5 Hz, 1H), 7.91 (s, 1H), 7.54-7.49 (m, 2H), 7.43-7.38 (m,2H), 6.68 (s, 1H), 3.81 (s, 2H), 3.55-3.53 (m, 4H), 2.45-2.43 (m, 4H);MS [M+H]⁺=564; LCMS RT=2.73.

Example 129 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 1 was used to preparethe title compound by substituting1-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]ureafor Intermediate O. ¹H-NMR (DMSO-d₆) δ 10.89-10.70 (br s, 1H), 10.42 (s,1H), 8.58 (d, J=5.2 Hz, 1H), 8.36 (d, J=8.7 Hz, 1H), 7.91 (s, 1H), 7.78(s, 1H), 7.57 (s, 1H), 7.42-7.37 (m, 2H), 6.69 (s, 1H), 3.81 (s, 2H),3.56-3.53 (m, 4H), 2.45-2.43 (m, 4H); MS [M+H]⁺=547; LCMS RT=2.47.

Example 130 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(3-bromophenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E and1-bromo-3-isocyanatobenzene for 2-fluoro-5-trifluoromethylphenylisocyanate. ¹H-NMR (DMSO-d₆) δ 9.61 (s, 1H), 8.43 (s, 1H), 8.23 (d,J=8.6 Hz, 1H), 7.91 (s, 1H), 7.90-7.89 (m, 1H), 7.53 (s, 1H), 7.38 (d,J=8.6 Hz, 1H), 7.29-7.23 (m, 2H), 7.18-7.16 (m, 1H), 6.67 (s, 1H), 3.81(s, 2H), 3.55-3.53 (m, 4H), 2.45-2.43 (m, 4H); MS [M+H]⁺=556; LCMSRT=2.63.

Example 131 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(3-chlorophenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E and1-chloro-3-isocyanatobenzene for 2-fluoro-5-trifluoromethylphenylisocyanate. ¹H-NMR (DMSO-d₆) δ 9.73 (s, 1H), 8.54 (s, 1H), 8.32 (d,J=7.8 Hz, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 7.47 (d, J=8.2Hz, 1H), 7.42 (t, J=8.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.3Hz, 1H), 6.77 (s, 1H), 3.90 (s, 2H), 3.65-3.62 (m, 4H), 2.55-2.51 (m,4H); MS [M+H]⁺=512; LCMS RT=2.44.

Example 132 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(3-methoxyphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E and1-isocyanato-3-methoxybenzene for 2-fluoro-5-trifluoromethylphenylisocyanate. ¹H-NMR (DMSO-d₆) δ 9.50 (s, 1H), 8.43 (s, 1H), 8.30 (d,J=8.4 Hz, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.42 (d, J=8.3 Hz, 1H),7.26-7.22 (m, 2H), 6.99 (d, J=8.6 Hz, 1H), 6.72 (s, 1H), 6.62 (d, J=7.8Hz, 1H), 3.85 (s, 2H), 3.77 (s, 3H), 3.60-3.58 (m, 4H), 2.50-2.48 (m,4H); MS [M+H]⁺=508; LCMS RT=2.25.

Example 133 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(4-methylpyridin-2-yl)urea

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting Intermediate Y for Intermediate E andphenyl(4-methylpyridin-2-yl)carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate. ¹H-NMR (DMSO-d₆) δ 10.05 (s,1H), 8.50 (d, J=9.5 Hz, 1H), 8.24 (d, J=5.0 Hz, 1H), 7.98 (s, 1H), 7.63(s, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.07 (s, 1H), 6.96-6.94 (m, 1H), 6.75(s, 1H), 3.88 (s, 2H), 3.63-3.60 (m, 4H), 2.63-2.59 (m, 4H), 2.35 (s,3H); MS [M+H]⁺=493; LCMS RT=2.03.

Example 134 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(3-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E and1-isocyanato-3-methylbenzene for 2-fluoro-5-trifluoromethylphenylisocyanate. ¹H-NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.37 (s, 1H), 8.26 (d,J=8.6 Hz, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.32(s, 1H), 7.24 (d, J=7.4 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H), 6.81 (d, J=7.4Hz, 1H), 6.67 (s, 1H), 3.81 (s, 2H), 3.57-3.52 (m, 4H), 2.45-2.42 (m,4H), 2.28 (s, 3H); MS [M+H]⁺=492; LCMS RT=2.52.

Example 135 Preparation ofN-4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl-N′-(2-fluoro-5-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate Y for Intermediate E and1-fluoro-2-isocyanato-4-methylbenzene for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.34 (s,1H), 8.87 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.91(s, 1H), 7.53 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.14-7.09 (m, 1H),6.84-6.80 (m, 1H), 6.68 (s, 1H), 3.81 (s, 2H), 3.56-3.54 (m, 4H),2.46-2.43 (m, 4H), 2.27 (s, 3H); MS [M+H]⁺=510; LCMS RT=2.56.

Example 136 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-[2-fluoro-5(trifluoromethyl)-phenyl]urea

A solution of Intermediate C and Intermediate AA in DMF (2 mL) wasdegassed. To that was added Tetrakis(triphenylphosphine)palladium(0).The reaction vial was sealed and heated to 80° C. for 12 h. The reactionmixture was filtered through a 0.5 micron frit and purified by HPLC. Theisolated fractions were concentrated in vacuo and the resulting solidswere diluted with EtOAc (50 mL) and washed with saturated NaHCO₃. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. MS[M+H]⁺=562.0; LCMS RT=2.56.

Example 137 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-chlorophenyl)urea

To a solution of Intermediate G (80 mg, 0.205 mmol) and1-chloro-3-isocyanatobenzene (47 mg, 0.307 mmol) in THF (4 mL) was addedtriethylamine (86 μL, 0.615 mmol). The solution was heated and stirredover 12 h. The reaction mixture was concentrated in vacuo to provide athick oil. The residue was dissolved in DMF (3 ml) and 2N HCl (2 mL) wasadded. The mixture was heated at 88° C. for 1 h. The reaction mixturewas cooled to rt and the solvent was concentrated in vacuo. The compoundwas loaded onto silica gel and flashed beginning at 2% THF in DCM andending at 90% TBF in DCM. The pure fractions were combined andconcentrated in vacuo. The white solid that forned on the flask waswashed with ether and ethyl acetate to remove traces of BHT and anyslight impurities. The white solid was filtered and dried under vacuumwith heat (40° C.) to provide the title product (6 mg, 5% yield). ¹H-NMR(DMSO-d₆) δ 9.28 (s, 1H), 8.71 (d, J=2.8, 1H), 8.22 (t, J=8.8, 1H), 7.92(s, 1H), 7.74 (t, J=2.0, 1H), 7.35 to 7.31 (m, 2H), 7.24 (dd, J=8.4,0.8, 2H), 7.05 to 7.03 (m, 1H), 6.73 (s, 1H), 4.02 (s, 2H), 3.11 to 3.09(m, 4H), 2.96 to 2.93 (m, 4H); MS [M+H]⁺=544.2; LCMS RT=2.76.

Example 138 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 137, using1-chloro-2-isocyanato-4-(trifluoromethyl)benzene in place of1-chloro-3-isocyanatobenzene. 10 mg (8%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.63 (s, 1H), 9.13 (s, 1H), 8.63 (d, J=2.4,1H), 8.28 (t, J=8.4, 1H), 7.92 (s, 1H), 7.74 (d, J=8.4, 1H), 7.39 (dd,J=8.8, 2.4, 1H), 7.35 (dd, J=12.0, 1.6, 1H), 7.25 (dd, J=8.4, 2.0, 1H),6.74 (s, 1H), 4.02 (s, 2H), 3.11 to 3.09 (m, 4H), 2.96 to 2.93 (m, 4H);MS [M+H]⁺=612.2; LCMS RT=3.01.

Example 139 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(4-tert-butylpyridin-2-yl)urea

To a solution of Intermediate G (80 mg, 0.205 mmol) and phenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (61 mg, 0.225 mmol) in THF (4mL) was added triethylamine (29 μL, 0.205 mmol). The solution was heatedto 60° C. and stirred over 12 h. The reaction mixture was concentratedin vacuo to provide a thick oil. Upon cooling the reaction mixture tort, the product crashed out of solution. The white solid was filteredand washed with ether and ethyl acetate to remove traces of BHT and anyslight impurities. The white solid was dried under vacuum with heat (40°C.) to provide the title product (18 mg, 16% yield). ¹H-NMR (DMSO-d₆) δ9.79 (s, 1H), 8.35 (t, J=8.8, 1H), 8.17 (d, J=5.2, 1H), 7.92 (s, 1H),7.40 to 7.36 (m, 1H), 7.35 (dd, J=12.0, 2.0, 1H), 7.24 (dd, J=8.8, 1.6,1H), 7.08 (dd, J=5.6, 1.6, 1H), 6.74 (s, 1H), 4.03 (s, 2H), 3.12 to 3.09(m, 4H), 2.96 to 2.93 (m, 4H), 1.25 (s, 9H); MS [M+H]⁺=567.2; LCMSRT=2.67.

Example 140 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(4-methylpyridin-2-yl)urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 137, usingphenyl(4-methylpyridin-2-yl)carbamate in place ofphenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate. 16 mg (17%) of thedesired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.85 (s, 1H), 8.31 (t,J=8.4, 1H), 8.12 (d, J=5.2, 1H), 7.91 (s, 1H), 7.35 (dd, J=12.4, 2.0,1H), 7.25 (dd, J=8.8, 2.0, 1H), 7.19 to 7.15 (m, 1H), 6.87 (dd, J=5.2,1.6, 1H), 6.74 (s, 1H), 4.02 (s, 2H), 3.12 to 3.09 (m, 4H), 2.96 to 2.93(m, 4H), 2.28 (s, 3H); MS [M+H]⁺=525.1; LCMS RT=2.28.

Example 141 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 137, using1-fluoro-2-isocyanato-4-methylbenzene in place of1-chloro-3-isocyanatobenzene. 10 mg (9%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.12 (d, J=2.8, 1H), 9.01 (d, J=2.8, 1H),8.27 (t, J=8.8, 1H), 8.02 (dd, J=7.2, 1.6, 1H), 7.91 (s, 1H), 7.32 (dd,J=12.0, 2.0, 1H), 7.23 (dd, J=8.4, 1.6, 1H), 7.11 (dd, J=11.2, 8.0, 1H),6.83 to 6.78 (m, 1H), 6.73 (s, 1H), 4.02 (s, 2H), 3.12 to 3.09 (m, 4H),2.96 to 2.93 (m, 4H), 2.26 (s, 3H); MS [M+H]⁺=542.2; LCMS RT=2.72.

Example 142 Preparation ofN-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3,4-dichlorophenyl)urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 137, using1,2-dichloro-4-isocyanatobenzene in place of1-chloro-3-isocyanatobenzene. 8 mg (8%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 11.01 (s, 1H), 10.05 (s, 1H), 8.03 (t,J=9.2, 1H), 7.94 (d, J=2.4, 1H), 7.91 (s, 1H), 7.49 (d, J=8.4, 1H), 7.41(dd, J=8.8, 2.0, 1H), 7.29 (dd, J=12.0, 1.6, 1H), 7.21 (dd, J=6.4, 2.0,1H), 6.74 (s, 1H), 4.02 (s, 2H), 3.11 to 3.09 (m, 4H), 2.96 to 2.93 (m,4H); MS [M+H]⁺=580.9; LCMS RT=2.81.

Example 143 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-chlorophenyl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting1-(3-chlorophenyl)-3-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (MeOD-d₄) δ 8.29-8.27 (m, 1H), 8.04 (s, 1H),7.70-7.69 (m, 1H), 7.30-7.26 (m, 3H), 7.06-7.04 (m, 1H), 7.03 (s, 1H),4.82 (s, 2H), 4.11-3.95 (m, 2H), 3.85-3.71 (m, 2H), 3.48-3.30 (m, 4H);MS [M+H]⁺=514.0; LCMS RT=2.46 min.

Example 144 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate, Intermediate AZ for Intermediate R. ¹H-NMR(DMSO-d₆) δ 9.93 (s, 1H), 9.34 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.18(dd, J=12, 7.2 Hz 1H), 7.95 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.45 (dd,J=8.4, 2.0 Hz, 1H), 7.36 (dd, J=11.6, 6.8 Hz 1H), 6.68 (s, 1H), 3.85 (s,2H), 3.40-3.37 (m, 4H), 2.48-2.46 (m, 4H); MS [M+H]⁺=582.2; LCMS RT=2.78min.

Example 145 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(2-fluoro-5-methylphenyl)ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (MeOD-d₄) δ 8.25-8.19 (m, 1H), 8.04 (s, 1H),7.98-7.95 (m, 1H), 7.30-7.23 (m, 1H), 7.05-6.97 (m, 2H), 7.88-6.83 (m,1H), 4.82 (s, 2H), 4.13-3.95 (m, 2H), 3.72-3.60 (m, 2H), 3.48-3.32 (m,4H), 2.32 (s, 3H); MS [M+H]⁺=512.1; LCMS RT=2.93 min.

Example 146 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-(2-fluoro-5-methylphenyl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,1-(2-fluoro-5-methylphenyl)-3-[2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.12 (d, J=2.4 Hz, 1H), 9.06 (d,J=2.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.02 (dd, J=8.0, 2.4 Hz 1H), 7.88(s, 1H), 7.13-7.07 (m, 2H), 6.80-7.91 (m, 1H), 6.53 (s, 1H), 3.81 (s,2H), 3.54 (t, J=4.4 Hz, 4H), 2.43 ((t, J=4.4 Hz, 4H), 2.26 (s, 3H), 2.10(s, 3H); MS [M+H]⁺=508.2; LCMS RT=2.83 min.

Example 147 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,1-[2-chloro-5-(trifluoromethyl)phenyl]-3-[2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (DMSO-d₆) δ 9.68 (s, 1H), 9.23 (s, 1H), 8.62(d, J=2.0 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.71 (d, J=8.4Hz, 1H), 7.38 (dd, J=8.4, 2.4 Hz, 1H), 7.14 (d, J=11.6 Hz, 1H), 6.53 (s,1H), 3.81 (s, 2H), 3.54 (t, J=4.4 Hz, 4H), 2.43 ((t, J=4.4 Hz, 4H), 2.11(s, 3H); MS [M+H]⁺=578.1; LCMS RT=3.06 min.

Example 148 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-(3-methylphenyl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,1-[2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(3-methylphenyl)ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (MeOD-d₄) δ 8.12-8.10 (m, 2H), 7.30-7.28 (m,2H), 7.18-7.12 (m, 2H), 7.00 (s, 1H), 6.87 (d, J=8.0 Hz, 1H), 4.81 (d,J=4.4 Hz, 2H), 4.09-3.75 (m, 4H), 3.48-3.33 (m, 4H), 2.33 (s, 3H), 2.20(s, 3H); MS [M+H]⁺=490.2; LCMS RT=2.28 min.

Example 149 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting 2-fluoro-5-methylphenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (DMSO-d₆) δ 9.19 (d,J=2.4 Hz, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.33 (t, J=8.8Hz, 1H), 8.10 (s,1H), 8.02 (dd, J=7.6, 1.6 Hz, 1H), 7.35 (dd, J=12, 2.0 Hz, 1H), 7.25(dd, J=8.0, 1.6 Hz, 1H), 7.13 (dd, J=11.2 , 8.0 Hz, 1H), 6.98 (s, 1H),6.84-6.81 (m, 1H), 4.73 (s, 2H), 4.0-3.92 (m, 2H), 3.69-3.58 (m, 2H),3.43-3.35 (m, 2H), 3.26-3.17 (m, 2H), 2.28 (s, 3H); MS [M+H]⁺=494.2;LCMS RT=2.54.

Example 150 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting 4-chloro-3-(trifluoromethyl)phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (MeOD-d₄) δ 8.25 (t,J=8.0 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=2.8 Hz, 1H), 7.62 (dd, J=8.8,2.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.36 (dd, J=11.6, 1.6 Hz, 1H),7.32-7.30 (m, 1H), 7.06 (s, 1H), 4.82 (s, 2H), 4.15-3.95 (m, 2H),3.89-3.70 (m, 2H), 3.49-3.32 (m, 4H); MS [M+H]⁺=564.0; LCMS RT=2.74.

Example 151 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting phenyl (4-tert-butylpyridin-2-yl)carbamate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (CD₃OD) δ 8.29 (t,J=8.4 Hz, 1H), 8.21 (d, J=6.4 Hz, 1H), 8.07 (s, 1H), 7.42-7.33 (m, 3H),7.28 (s, 1H), 7.06 (s, 1H), 4.82 (s, 2H), 4.11-3.62 (m, 4H), 3.49-3.33(m, 4H), 1.30 (s, 9H); MS [M+H]⁺=518.8; LCMS RT=2.26.

Example 152 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate, Intermediate BA for Intermediate R. ¹H-NMR(DMSO-d₆) δ 9.71 (s, 1H), 9.18 (s, 1H), 8.09 (dd, J=12, 6.8 Hz, 1H),7.92 (s, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.35-7.30 (m, 2H), 6.64 (s, 1H),3.82 (s, 2H), 3.56 (t, J=4.4 Hz, 4H), 2.45 (t, J=4.4 Hz, 4H); MS[M+H+=548.1; LCMS RT=3.00 min.

Example 153 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl]-N′-(4-tert-butylpyridin-2-yl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate, Intermediate BB for Intermediate R. ¹H-NMR(CD₃OD) δ 9.92 (σ, 1H), 8.26-8.20 (m, 2H), 8.07 (s, 1H), 7.37-7.32 (m,1H), 7.26 (s, 1H), 7.07 (s, 1H), 4.82 (s, 2H), 4.11-3.62 (m, 4H),3.49-3.33 (m, 4H), 1.37 (s, 9H); MS [M+H]⁺=537.0 LCMS RT=2.81 min.

Example 154 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-tert-butylphenyl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate, Intermediate AW for Intermediate R. ¹H-NMR(CD₃OD) δ 8.20 (dd, J=12, 6.8 Hz, 1H), 8.07 (s, 1H), 7.53-7.50 (m, 1H),7.31-7.21 (m, 3H), 7.32-7.11 (m, 1H), 7.06 (s, 1H), 4.82 (s, 2H),4.11-3.60 (m, 4H), 3.51-3.33 (m, 4H), 1.33 (s, 9H); MS [M+H]⁺=536.2;LCMS RT=2.85 min.

Example 155 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-ethylphenyl)urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(3ethylphenyl)ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (CD₃OD) δ 8.40 (s, 1H), 7.40-7.36 (m, 2H),7.25(t, J=7.6 Hz, 1H), 7.16 (dd, J=11.2, 6.8 Hz, 1H), 7.11 (s, 1H), 6.99(d, J=7.6 Hz, 1H), 6.75 (dd, J=11.6, 7.6 Hz, 1H), 4.86 (s, 2H),4.11-3.60 (m, 4H), 3.51-3.30 (m, 4H), 2.64 (q, J=7.6 Hz, 2H), 1.24 (t,J=7.6 Hz, 3H); MS [M+H]⁺=508.3; LCMS RT=3.10 min.

Example 156 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-ethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting 3-ethyl-phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (CD₃OD) δ 8.25(d,J=8.4 Hz, 1H), 8.08 (s, 1H), 7.36-7.15 (m, 5H), 7.06 (s, 1H), 6.90 (d,J=7.6 Hz, 1H), 4.82 (s, 2H), 4.11-3.60 (m, 4H), 3.51-3.30 (m, 4H), 2.63(q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H); MS [M+H]⁺=490.1; LCMSRT=2.50.

Example 157 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea

The title compound was prepared using the procedure to make Example 7 bysubstituting boronate,1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ureafor Intermediate R. The boronate was made using the procedure used tomake Intermediate R. ¹H-NMR (CD₃OD) δ 8.34 (s, 1H), 8.10 (s, 1H), 7.78(d, J=8.4 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.15 (dd, J=10.8, 6.4 Hz,1H), 7.10 (s, 1H), 6.73 (dd, J=11.2, 7.6 Hz, 1H), 4.85 (s, 2H),4.25-3.98 (m, 2H), 3.76-3.69 (m, 2H), 3.55-3.30 (m, 4H); MS[M+H]⁺=582.0; LCMS RT=3.17 min.

Example 158 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3,4-dichlorophenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting 3,4-dichloro-phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (CD₃OD) δ 8.24 (t,J=8.4 Hz, 1H), 8.06 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.43 (d, J=8.8 Hz,1H), 7.34 (dd, J=11.6, 2.0 Hz, 1H), 7.29 (dd, J=8.4, 2.4 Hz, 2H), 7.04(s, 1H), 4.81 (s, 2H), 4.25-3.98 (m, 2H), 3.76-3.69 (m, 2H), 3.55-3.30(m, 4H); MS [M+H]⁺=529.8; LCMS RT=2.55.

Example 159 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3,5-dimethylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting 3,5-dimethyl-phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (CD₃OD) δ 8.24 (t,J=8.4 Hz, 1H), 8.06 (s, 1H), 7.35-7.27 (m, 2H), 7.08 (s, 2H), 7.03 (s,1H), 6.71 (s, 1H), 4.81 (s, 2H), 4.11-3.75 (m, 4H), 3.48-3.24 (m, 4H),2.20 (s, 6H); MS [M+H]⁺=490.1; LCMS RT=2.50.

Example 160 Preparation ofN-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting Intermediate F for Intermediate E andby substituting 3-fluoro-5-(trifluoromethyl)phenyl isocyanate for2-fluoro-5-trifluoromethylphenyl isocyanate. ¹H-NMR (CD₃OD) δ 8.25 (t,J=8.4 Hz, 1H), 8.07 (s, 1H), 7.85 (dt, J=11.2, 1.6 Hz, 1H), 7.60 (s,1H), 7.36 (dd, J=11.6, 2.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.08 (dt, J=8.4,1.6 Hz, 1H), 7.05 (s, 1H), 4.81 (s, 2H), 4.25-3.98 (m, 2H), 3.76-3.69(m, 2H), 3.55-3.30 (m, 4H); MS [M+H]⁺=548.0; LCMS RT=2.69.

Example 161N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 282 was used toprepare the title compound by substituting 1-methylpiperazine fortert-butyl 2-(aminomethyl)morpholine4-carboxylate in step 2. ¹H-NMR(CD₃OD) δ 8.65 (d, J=7.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.92 (s, 1H),7.36-7.29 (m, 4H), 6.90 (s, 1H), 3.90-3.79 (m, 2H), 3.50-3.39 (m, 2H),2.62-2.43 (m, 4H), 2.35 (s, 3H); MS [M+H]⁺=575.1; LCMS RT=2.63 min.

Example 162 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea

Intermediate D (70 mg, 0.215 mmol) and Intermediate Q (127 mg, 0.301mmol) were added to a vial, dioxane (2 mL) was added followed by aq 1Nsodium carbonate (646 uL, 646 mmol). The reaction was then placed underN₂. The reaction was taken through 3 purge-fill cycles with N₂ andvacuum. Tetrakistriphenylphosphinepalladuium, (25 mg, 0.022 mmol) wasthen added. The reaction was degassed and then heated in an oil bath at80° C. for 16 h. The reaction mixture was partitioned between EtOAc (50mL) and H₂O (20 mL). There were solids between the layers. The solidswere collected by filtration then washed with EtOAc followed by H₂O. Thematerial was triturated with 25% CH₂Cl₂/MeOH to yield 19 mg (16%) cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.43 (s, 1H), 8.74 (s, 1H), 8.21 (t, J=5.7Hz, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.72 (s, 1H), 7.53 (m, 3H), 7.37 to7.23 (m, 2H), 6.70 (s, 1H), 3.87 (s, 2H), 3.30 (m, 2H), 2.60 (m, 2H); MS[M+H]⁺=543.0; LCMS RT=2.58 min

Example 163 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea

Intermediate D (70 mg, 0.215 mmol) and Intermediate AE (127 mg, 0.300mmol) were allowed to react using the procedure to make Example 162. Thesolid between the two layers was isolated and triturated in the mannerdescribed previously to yield 23 mg (20%) of pure desired product.¹H-NMR (DMSO-d₆) δ 10.12 (s, 1H), 10.06 (bs, 1H), 8.40 (d, J=5.1 Hz,1H), 8.27 (t, J=8.7 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.71 (s, 1H),7.38 to 7.25 (m, 3H), 6.71 (s, 1H), 3.91 (s, 2H), 3.17 (m, 2H), 2.59 (m,2H); MS [M+H]⁺=543.7; LCMS RT=2.38

Example 164 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate D (70 mg, 0.215 mmol) and Intermediate AH (138 mg, 0.300mmol) were allowed to react using the procedure to make Example 162 withsubstitution of DMF for dioxane. The reaction mixture was partitionedbetween EtOAc (100 mL) and H₂O (30 mL). The organic layer was thenwashed (6×20 mL) with brine to remove DMF. The organic layer was driedwith sodium sulfate then concentrated under vacuum. The residue ischromatographed on a MPLC 4 g Silica column. The product is eluted witha gradient of 0-6% Methanol/CH₂Cl₂ to yield 43 mg (35%) of clean desiredproduct. ¹H-NMR (DMSO-d₆) δ 9.48 (s, 1H), 8.44 (s, 1H), 8.63 (d, J=7.5Hz, 1H), 8.16 (dd, J=5.7, 6.9, 1H), 7.9 (s, 1H), 7.72 (s, 1H), 7.55 to7.31 (m, 3H), 6.67 (s, 1H), 3.91 (s, 2H), 2.62 (m, 2H); MS [M+H]⁺=578.9;LCMS RT=2.71

Example 165 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-methylphenyl)-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea

Intermediate D (70 mg, 0.215 mmol) and Intermediate AF (132 mg, 0.301mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed on a MPLC 4 g Silica column. The product waseluted with a gradient of 0-6% Methanol/CH₂Cl₂ to yield 64 mg (53%) ofclean desired product. ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 8.67 (d, J=7.5Hz, 1H), 8.58 (bs, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.72 (bs,1H), 7.54 to 7.25 (m, 3H), 6.66 (s, 1H), 3.91 (s, 2H), 3.11 (m, 2H),2.63 (m, 2H), 2.31 (s, 3H); MS [M+H]⁺=556.8 ; LCMS RT=2.44

Example 166 Preparation ofN-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea

Intermediate D (75 mg, 0.232 mmol) and Intermediate AI (125 mg, 0.323mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed on a MPLC 4 g Silica column. The product waseluted with a gradient of 0-6% Methanol/CH₂Cl₂ to yield 69 mg (59%) ofclean desired product. ¹H-NMR (DMSO-d₆) δ 9.12 (s, 1H), 9.01 (s, 1H),8.27 (t, J=8.7 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H), 7.92 (s, 1H), 7.36-7.08(m, 3H), 6.83 (m, 1H), 6.71 (s, 1H), 3.91 (s, 2H), 3.13 (m, 2H), 2.63(m, 2H), 2.27 (s, 3H); MS [M+H]⁺=506.8; LCMS RT=2.30.

Example 167 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate Z (75 mg, 0.231 mmol) and Intermediate M (132 mg, 0.301mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed on a MPLC 4 g Silica column. The product waseluted with a gradient of 0-6% Methanol/CH₂Cl₂ to yield 64 mg (53%) ofclean desired product. ¹H-NMR (DMSO-d₆) δ 9.31 (s, 1H), 8.94 (s, 1H),8.63 (dd, J=7.2 Hz, J=2.1 Hz, 1H), 7.90 (s, 1H), 7.62 to 7.39 (m, 6H),6.63 (s, 1H), 3.99 (s, 2H), 3.69 to 3.41 (m, 4H), 2.71 (m, 2H), 1.80 (t,J=5.1, 2H); MS [M+H]⁺=544.1; LCMS RT=2.49.

Example 168 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate Z (150 mg, 0.345 mmol) and Intermediate AH (206 mg, 0.448mmol) were allowed to react using the procedure to make Example 162. Theaqueous layer was back extracted with EtOAc (25 mL). The combinedorganic layer was washed with brine then dried with Na₂SO₄. The residuewas chromatographed using a 4 g MPLC column. The product was eluted witha gradient of 0-10% MeOH/CH₂Cl₂ to yield 87 mg (44%) clean product.¹H-NMR (DMSO-d₆) δ 9.48 (s, 1H), 9.44 (s, 1H), 8.63 (dd, J=4.5 Hz, J=2.4Hz, 1H), 7.91 (s, 1H), 7.652 to 7.30 (m, 3H), 6.64 (s, 1H), 3.98 (s,2H), 3.68 to 3.58 (m, 4H), 2.70 (m, 4H), 1.79 (m, 2H); MS [M+H]⁺=580.1;LCMS RT=2.61.

Example 169 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea

Intermediate Z and Intermediate AM (206 mg, 0.448 mmol) were allowed toreact using the procedure to make Example 164. The residue waschromatographed using a 4 g MPLC column. The product was eluted with agradient of 0-10% MeOH/CH₂Cl₂ to yield 3 mg (1.8%) clean product ¹H-NMR(Methanol-d₄) δ 8.31 (t, J=8.1 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.84 (s,1H), 7.28 (m, 2H), 7.11 (s, 1H), 7.03 (m, 1H), 6.71 (s, 1H), 4.06 (s,2H), 3.80 to 3.72 (m, 4H), 2.85 to 2.76 (m, 4H), 1.97 to 1.89 (m, 2H),1.39 (s, 9H); MS [M+H]⁺=533.0; LCMS RT=2.30.

Example 170 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea

Intermediate Z and Intermediate BB (172 mg, 0.399 mmol) were allowed toreact using the procedure to make Example 164. The residue waschromatographed using a 4 g MPLC column. The product was eluted with agradient of 0-10% (2N NH₃ in MeOH)/CH₂Cl₂ to yield 9 mg (5%) cleanproduct ¹H-NMR (DMSO-d₆) δ 9.90 (s, 1H), 8.24 to 8.17 (m, 3H), 7.91 (s,1H), 7.39 to 7.30 (m, 2H), 7.10 (dd, J=4.8 Hz, J=1.8 Hz 1H), 6.65 (s,1H), 3.98 (s, 2H), 3.68 to 3.58 (m, 4H), 2.72 to 2.67 (m, 4H), 1.81 to1.78 (m, 2H), 1.24 (m, 9H); MS [M+H]⁺=551.0; LCMS RT=2.44.

Example 171 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

Intermediate Z and Intermediate AJ (155 mg, 0.339 mmol) were allowed toreact using the procedure to make Example 164. The residue waschromatographed using a 4 g MPLC column. The product was eluted with agradient of 0-6% MeOH/CH₂Cl₂ to yield 34 mg (23%) of clean product.¹H-NMR (DMSO-d₆) δ 9.62 (s, 1H), 9.13 (s, 1H), 8.65 (s, 1H), 8.25 (t,J=8.7 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.41 to 7.23 (m,3H), 6.68 (s, 1H), 3.98 (s, 2H), 3.68 to 3.58 (m, 4H), 2.72 to 2.67 (m,4H), 1.81 to 1.78 (m, 2H); MS [M+H]⁺=578.0; LCMS RT=2.99.

Example 172 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-chlorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate AQ (149 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 31 mg (21%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.79 (s, 1H), 8.48 (s, 1H), 8.65 (d, J=4.8Hz, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.91 (s, 1H), 7.55 (m, 3H), 7.42 to7.36 (m, 2H), 6.69 (s, 1H), 3.98 (s, 2H), 3.68 to 3.58 (m, 4H), 2.72 to2.68 (m, 4H), 1.79 (t, J=5.4 Hz, 2H); MS [M+H]⁺=560.0; LCMS RT=2.96.

Example 173N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using glycolic acid inplace of sodium 2-hydroxypropanoate, 36 mg (65%) of the desired productwas isolated. ¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.4 Hz, 1H), 9.01 (s, 1H),8.65 (dd, J=2.1, 7.2 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.91 (s, 1H),7.54-7.48 (m, 2H), 7.43-7.35 (m, 2H), 6.60 (s, 1H), 4.51 (t, J=5.4 Hz,1H), 4.12-4.09 (m, 2H), 3.84-3.72 (m, 1H), 3.49-3.32 (m, 1H), 3.15-3.03(m, 2H), 2.82-2.71 (m, 1H), 2.04-1.97 (m, 2H), 1.73-1.48 (m, 2H); MS[M+H]⁺=606.3, 608.3; LCMS RT=2.91 min.

Example 174 Preparation of1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-(4-fluoro-3-methylphenyl)urea

Intermediate Z (85 mg, 0.307 mmol) and Intermediate BD (132 mg, 0.5339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 3 mg (2%) of cleanproduct. ¹H-NMR (Methanol-d₄) δ 9.05 (s, 1H), 8.62 (s, 1H), 8.25 (t,J=8.7 Hz, 1H), 7.90 (s, 1H), 7.35 to 7.19 (m, 4H), 6.67 (s, 1H), 3.98(s, 2H), 3.68 to 3.58 (m, 4H), 2.73 to 2.50 (m, 7H), 1.80 (m, 2H); MS[M+H]⁺=508.0; LCMS RT=2.31.

Example 175 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-ethylphenyl)urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate BE (130 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 43 mg (33%) of cleanproduct. MS [M+H]⁺=504.0; LCMS RT=2.39.

Example 176 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-ylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Intermediate Z (100 mg, 0.307 mmol) and Intermediate AD (174 mg, 0.429mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-20% (1:1 THF-MeOH)/CH₂Cl₂ to yield 30 mg(19%) of clean product. ¹H-NMR (DMSO-d₆) δ 9.87 (s, 1H), 9.74 (s, 1H),8.54 (d, J=5.1 Hz, 1H), 8.06 (t, 1H), 7.90 (s, 1H), 7.62 (d, J=5.4 Hz,2H), 7.43 to 7.36 (m, 3H), 6.64(s, 1H), 3.99 (s, 2H), 3.68 to 3.59 (m,4H), 2.72 to 2.69 (m, 4H), 1.81 to 1.80 (m, 2H); MS [M+H]⁺=526.9; LCMSRT=2.46.

Example 177 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate O (150 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 60 mg (41%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.87 (s, 1H), 9.74 (s, 1H), 8.54 (d, J=5.1Hz, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.62 (d, J=5.4 Hz, 2H), 7.43 to7.36 (m, 3H), 6.64 (s, 1H), 3.99 (s, 2H), 3.68 to 3.59 (m, 4H), 2.72 to2.69 (m, 4H), 1.81 to 1.80 (m, 2H); MS [M+H]⁺=561.9; LCMS RT=2.61.

Example 178 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate Q (144 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 23 mg (16%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.44 (s, 1H), 8.74 (s, 1H), 8.22 (t, J=8.4Hz, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.55 to 7.23 (m, 5H), 6.68 (s, 1H),3.98 (s, 2H), 3.68 to 3.58 (m, 4H), 2.72 to 2.67 (m, 4H), 1.80 (m, 2H);MS [M+H]⁺=544.0; LCMS RT=2.51.

Example 179 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate AE (144 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 32 mg (23%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 10.13 (s, 1H), 10.05 (bs, 1H), 8.55 (d,J=8.1 Hz, 1H), 8.28 (t, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39to 7.25 (m, 3H), 6.69 (s, 1H), 3.98 (s, 2H), 3.68 to 3.58 (m, 4H), 2.72to 2.67 (m, 4H), 1.80 (m, 2H); MS [M+H]⁺=545.0; LCMS RT=2.42.

Example 180 Preparation of1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate AG (144 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 5.7 mg (3%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 10.17 (s, 1H), 9.95 (bs, 1H), 8.55 (d, J=7.5Hz, 1H), 8.09 (t, J=8.4 Hz, 1H), 7.89 to 7.87(m, 2H), 7.37 to 7.26 (m,3H), 6.63 (s, 1H), 3.96 (s, 2H), 3.68 to 3.56 (m, 4H), 2.72 to 2.60 (m,4H), 2.32 (s, 3H), 1.79 (m, 2H); MS [M+H]⁺=541.0; LCMS RT=2.45

Example 181 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate Z (85 mg, 0.261 mmol) and Intermediate AF (148 mg, 0.339mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 21 mg (14%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.57(s, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.89 (s, 1H), 7.51 to 7.25 (m, 4H),6.63 (s, 1H), 3.99 (s, 2H), 3.68 to 3.56 (m, 4H), 2.72 to 2.67 (m, 4H),1.78 (m, 2H); MS [M+H]⁺=558.0; LCMS RT=2.50

Example 182 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea

Intermediate Z (100 mg, 0.307 mmol) and Intermediate AP (162 mg, 0.399mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 20 mg (12%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.80 (s, 1H), 9.20 (d, J=3.9 Hz, 1H), 8.61(s, 1H), 8.14 (dd, J=7.2, J=12.0 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=8.4Hz, 1H), 6.64 (s, 1H), 3.98 (s, 2H), 3.65 to 3.57 (m, 4H), 3.29 (s, 3H),2.71 to 2.68 (m, 4H), 1.79 (t, J=5.7, 2H); MS M+H]⁺=526.2; LCMS RT=2.44.

Example 183 Preparation ofN-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea

Intermediate Z (100 mg, 0.307 mmol) and Intermediate AT (148 mg, 0.399mmol) were allowed to react using the procedure to make Example 164. Theresidue was chromatographed using a 4 g MPLC column. The product waseluted with a gradient of 0-6% MeOH/CH₂Cl₂ to yield 30 mg (20%) of cleanproduct. ¹H-NMR (DMSO-d₆) δ 9.17 (s, 1H), 8.51 (s, 1H), 7.99 (dd, J=8.1Hz, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.55 (m, 2H), 7.38 (m, 2H), 7.10 (dd,J=11.4 Hz, J=8.1 Hz, 1H), 6.72 (m, 1H), 6.62 (s, 1H), 3.97 (s, 2H), 3.67to 3.57 (m, 4H), 3.29 (s, 3H), 2.68 (m, 4H), 2.26 (s, 3H), 1.79 (m, 2H).

Example 184 Preparation ofN-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(Example 193 step 1) (50 mg, 0.088 mmol) and(2S)-2-(methoxymethyl)pyrrolidine (36 uL, 0.263 mmol) were added to avial. DMF was added (1 mL) followed by triethylamine (15 uL, 0.109 mmol)and KI (spatula tip). The vial was capped and the reaction heated at 55°C. for two hours. Upon cooling the product precipitated out of solution.The solids were collected by filtration and rinsed with ether to yield35 mg (65%) of clean product. 1H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.25 (s,1H), 8.65 (d, J=7.2 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55to 7.21 (m, 4H), 6.57 (s, 1H), 3.32 (s, 3H), 3.18 to 2.83 (m, 7H), 2.37to 1.45 (m, 5H); MS [M+H]⁺=604.2; LCMS RT=2.59

Example 185 Preparation ofN-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,5-difluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Synthesis of5-bromo-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine

Intermediate V step 4 (947 mg, 2.8 mmol) was allowed to react with(2S)-2-(methoxymethyl)pyrrolidine (980 mg, 8.5 mmol) using the procedureto make5-bromo-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine.The reaction was partitioned between EtOAc (100 mL) and saturatedaqueous sodium bicarbonate (20 mL). The aqueous layer was extracted withEtOAc (10 mL). The combined organic layer was washed with brine (10 mL)then dried with sodium sulfate. The reaction was concentrated undervacuum to quantitatively yield crude product. ¹H-NMR (DMSO-d₆) δ 7.83(s, 1H), 6.61 (s, 1H), 3.25 (m, 1H), 3.19 (s, 3H), 3.12 to 2.72 (m, 6H),2.23 (m, 1H), 2.04 (m, 1H), 1.77 (m, 3H), 1.62 (m, 2H), 1.40 (m, 1H); MS[M+H]⁺=622.2; LCMS RT=2.68.

Step 2: Preparation of the Title Compound

Intermediate AH (146 mg, 0.318 mmol) and5-bromo-7-{3-[(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine(90 mg, 0.244 mmol) were allowed to react using the procedure to makeExample 164. The product was purified by column chromatography using a 4g MPLC column. The eluent was 0-6% (2N NH3 in MeOH)/CH₂Cl₂ to yieldclean product (18 mg, 9%) ¹H-NMR (DMSO-₆) δ 9.48 (s, 1H), 9.44 (s, 1H),8.67 (d, J=7.5 Hz, 1H), 8.14 (m, 1H), 7.89 (s, 1H), 7.53 to 7.26 (m,3H), 6.54 (s, 1H), 3.27 (m, 1H), 3.19 (s, 3H), 3.13 to 2.83 (m, 6H),2.26 (m, 1H), 2.07 (m, 1H), 1.82 (m, 3H), 1.64 (m, 2H), 1.40 (m, 1H); MS[M+H]⁺=622.2; LCMS RT=2.68.

Example 186 Preparation ofN-{4-[4-amino-7-(3-pyrrolidin-1-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting pyrrolidine for 1,4-oxazepane. The product was purified bycolumn chromatography using a 4 g MPLC column. The eluent was 0-10.0%(2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product (10 mg, 20%) ¹H-NMR(Methanol-d₄) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.67 (dd, J=7.2 Hz, J=2.4Hz, 1H), 8.26 (t, J×8.7 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.22 (m, 3H),6.58 (s, 1H), 2.89 (t, J=7.5 Hz, 2H), 2.40 (m, 6H), 1.84 (m, 2H), 1.65(m, 4H); MS [M+H]⁺=560.2; LCMS RT=2.61

Example 187 Preparation ofN-(4-{4-amino-7-[3-(4-methylpiperazin-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting 1-methylpiperazine for 1,4-oxazepane. The product waspurified by column chromatography using a 4 g MPLC column. The eluentwas 0-10.0% (2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product (15 mg, 29%)¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.66 (m, 1H), 8.25 (t,J=8.7 Hz, 1H), 7.89 (s, 1H), 7.52 to 7.22 (m, 4H), 6.57 (s, 1H), 2.85(t, J=7.8 Hz, 2H), 2.42 to 2.12 (m, 11H), 1.82 (m, 2H); MS [M+H]⁺=589.2;LCMS RT=2.44

Example 188 Preparation ofN-(4-{7-[3-(4-acetylpiperazin-1-yl)propyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting 1-acetylpiperazine for 1,4-oxazepane. Upon cooling theproduct precipitated out of solution. The solids were collected byfiltration and rinsed with ether to yield (35 mg, 65%) 1H-NMR (DMSO-d₆)δ 9.41 (s, 1H), 9.25 (s, 1H), 8.66 (d, J=6.3 Hz, 1H), 8.26 (t, J=8.7 Hz,1H), 7.89 (s, 1H), 7.52 to 7.22 (m, 4H), 6.59 (s, 1H), 3.39 (m, 4H),2.88 (m, 2H), 2.72 to 2.27 (m, 5H), 1.97 (s, 1H), 1.85 (t, J=7.2 Hz,2H).

Example 189 Preparation ofN-(4-{4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting thiomorpholine 1,1-dioxide for 1,4-oxazepane. Upon coolingthe product precipitated out of solution. The product was purified bycolumn chromatography using a 4 g MPLC column.

The eluent was 0-10.0% (2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product(10 mg, 19%) ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.26 (s,1H), 8.26 (t,J=8.4 Hz, 1H), 7.89 (s, 1H), 7.35 to 7.30 (m, 4H), 6.60 (s, 1H), 3.05(m, 4H), 2.88 (m, 4H), 2.57 (m, 2H), 1.86 (m, 4H), MS [M+H]⁺624.1=; LCMSRT=2.72

Example 190 Preparation ofN-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate V (70 mg, 0.206 mmol) and Intermediate AH (142 mg, 0.309mmol) were added to a vial, Dioxane (3 mL) was added followed by Aq 1Nsodium carbonate (0.620 mL, 0.620 mmol). The reaction was then placedunder N₂. Reaction was taken through 3 purge-fill cycles with N₂ andVacuum. Tetrakistriphenylphosphinepalladuium, (24 mg, 0.021 mmol) wasthen added and the reaction degassed using vacuum and filled with N₂then heated in an oil bath at 90° C. overnight. The reaction mixture waspartitioned between EtOAc (75 mL) and H₂O (30 mL). The aqueous layer wasback extracted with EtOAc (25 mL). The combined organic layer was washedwith brine then dried with Na₂SO₄. After concentration, the residue waspurified by preparative HPLC using a gradient elution from 10% to 70%acetonitrile to obtain 16 mg, (13%) clean product. ¹H-NMR (DMSO-d₆)□9.49 (s, 1H), 9.46 (s, 1H), 8.63 (m, 1H), 8.15 (dd, J=11.7 Hz, J=6.9Hz, 1H), 7.90 (s, 1H), 7.57 to 7.27 (m, 3H), 6.55 (s, 1H), 3.55 (m, 4H),3.68 to 3.58 (m, 4H), 2.88 (t, J=7.5 Hz, 2H), 2.30 (m, 6H), 1.82 (m,2H); MS [M+H]⁺=594.2; LCMS RT=2.65.

Example 191 Preparation ofN-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Intermediate V (70 mg, 0.206 mmol) and Intermediate AE (131 mg, 0.309mmol) was allowed to react using the procedure to make Example 190. Thematerial was purified by column chromatography, eluent; 0-10%MeOH/CH₂Cl₂, followed by preparative HPLC, eluent; 10% to 70%acetonitrile to obtain 18 mg, (16%) clean product. ¹H-NMR (DMSO-d₆) δ10.13 (s, 1H), 10.05 (bs, 1H), 8.55 (d, J=5.7 Hz, 1H), 8.27 (t, J=8.4Hz, 1H), 8.01 (s, 1H), 7.89 (s, 1H), 7.40 to 7.23 (m, 3H), 6.58 (s, 1H),3.55 (m, 4H), 2.88 (m, 2H), 2.38 (m, 6H), 1.86 (m, 2H); MS [M+H]⁺=558.8;LCMS RT=2.31

Example 192 Preparation ofN-{4-[4-amino-7-(3-hydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Intermediate V step 3 (800 mg, 2.95 mmol) and Intermediate O (1.44 g,3.25 mmol) were added to a flask, Dioxane (35 mL) was added followed byAq 1N Sodium Carbonate (8.85 mL, 8.85 mmol). The reaction was thenplaced under N₂. Reaction was taken through 3 purge-fill cycles with N₂and Vacuum. Tetrakistriphenylphosphinepalladuium, (341 mg, 0.295 mmol)was then added and the reaction degassed using vacuum and filled with N₂then heated in an oil bath at 80° C. overnight. The reaction mixture waspartitioned between EtOAc (400 mL) and saturated sodium bicarbonate (80mL). The aqueous layer was back extracted with EtOAc (100 mL). Thecombined organic layer was washed with brine then dried with Na₂SO₄After concentration, the residue was purified by column chromatographyusing a gradient elution from 0% to 10% Methanol-CH₂Cl₂ to obtain 1.03g, (69%) of clean product. MS [M+H]⁺=507.3; LCMS RT=2.75 min

Example 193 Preparation ofN-(4-{4-amino-7-[3-(1,4-oxazepan-4-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 212step 3 by substitutingN-{4-[4amino-7-(3-hydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]ureafor1-(4-[4-amino-7-(2-hydroxyethyl)-pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea.MS [M+H]⁺=569.2; LCMS RT=3.44

Step 2: Preparation of the Title Compound

1-{4-[4-amino-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(50 mg, 0.088 mmol) and 1,4-oxazepane (36 mg, 0.263 mmol) were allowedto react using the procedure to makeN-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.The product was purified by column chromatography using a 4 g MPLCcolumn. The eluent was 0-10.0% (2N NH₃ in MeOH)/CH₂Cl₂ to yield cleanproduct (11 mg, 22%) ¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.66(m, 1H), 8.26 (t, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.52 to 7.22 (m, 4H),6.58 (s, 1H), 3.66 to 3.56 (m, 4H), 2.90 to 2.42 (m, 8H), 2.57 (m, 2H),1.79 (m, 4H), MS [M+H]⁺=590.2; LCMS RT=2.61

Example 194 Preparation ofN-(4-{4-amino-7-[3-(dimethylamino)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting N-methylmethanamine (2N in THF) for 1,4-oxazepane. Theproduct is purified by column chromatography using a 4 g MPLC column.The eluent was 0-10.0% (2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product(26 mg, 56%) MS [M+H]⁺=534.1; LCMS RT=2.49.

Example 195 Preparation ofN-(4-{4-amino-7-[3-(3-oxopiperazin-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting piperazin-2-one for 1,4-oxazepane. The product was purifiedby column chromatography using a 4 g MPLC column. The eluent was 0-10.0%(2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product (14 mg, 27%) ¹H-NMR(Methanol-d₄) δ 8.67 (m, 1H), 8.27 (m, 1H), 7.89 (s, 1H), 7.49 to 7.22(m, 4H), 6.59 (s, 1H), 3.37 (m, 8H), 3.10 (m, 4H), 2.91 (m, 2H), 1.86(m, 4H), MS [M+H]⁺=589.2; LCMS RT=2.53

Example 196 Preparation ofN-{4-4-[4-amino-7-(3-thiomorpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting thiomorpholine for 1,4-oxazepane. The product was purifiedby column chromatography using a 4 g MPLC column. The eluent was 0-10.0%(2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product (18 mg, 35%) ¹H-NMR(DMSO-d₆) δ 9.41 (s, 1H), 9.25 (s, 1H), 8.65 (dd, J=7.2, Hz, J=2.1 Hz,1H), 8.25 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.52 to 7.22 (m, 4H), 6.57(s, 1H), 2.85 (t, J=8.4 Hz, 2H), 2.61 (m, 8H), 2.38 (m, 2H), 1.86 (m,2H), MS [M+H]⁺=592.2; LCMS RT=2.49 NMR

Example 197 Preparation ofN-[4-(4-amino-7-{3-[ethyl(2-hydroxyethyl)amino]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a mannor analogous to Example 193 bysubstituting 2-(ethylamino)ethanol for 1,4-oxazepane. The product waspurified by column chromatography using a 4 g MPLC column. The eluentwas 0-10.0% (2N NH₃ in MeOH)/CH₂Cl₂ to yield clean product (15 mg, 24%)¹H-NMR (DMSO-d₆) δ 9.41 (s, 1H), 9.26 (s, 1H), 8.67 (dd, J=7.5, Hz,J=2.4 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.55 to 7.22 (m,4H), 6.58 (s, 1H), 4.29 (m, 1H), 3.43 (m, 2H), 3.38 to 3.15 (m, 6H),1.79 (m, 2H), 0.93 (t, J=6.6 Hz, 3H), MS [M+H]⁺=578.2; LCMS RT=2.42

Example 198 Preparation of tert-butyl3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate

Intermediate AB (431 mg, 1.13 mmol) and Intermediate O (600 mg, 1.41mmol) were added to a vial, DMF (2 mL) was added followed by K₃PO₄ (719mg, 3.39 mmol) and water (200 uL). The reaction was then placed underN₂. Reaction was taken through 3 purge-fill cycles with N₂ and Vacuum.Tetrakistriphenylphosphine palladuium, (129 mg, 0.112 mmol) was thenadded and the reaction degassed using vacuum and filled with N₂ thenheated in an oil bath at 110° C. for 2 hours. The reaction mixture waspartitioned between EtOAc (150 mL) and H₂O (70 mL). The aqueous layerwas back extracted with EtOAc (50 mL). The combined organic layer waswashed with brine then dried with Na₂SO₄. The residue waschromatographed using a 40 g MPLC column. The product was eluted with agradient of 0-6% MeOH/CH₂Cl₂ then was recrystallized from EtOAc/hexanesto yield 82 mg (12%) clean product. ¹H-NMR (DMSO-d₆) δ 10.12 (s, 1H),10.05 (s, 1H), 8.53 (d, J=3.6, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.91 (s,1H), 7.38 to 7.23 (m, 2H), 6.65(s, 1H), 3.75 (m, 2H), 3.45 to 3.24 (m,2H), 2.27(m, 1H), 2.08 (m, 1H), 1.38 (s, 9H); MS [M+H]⁺=601.2; LCMSRT=3.27

Example 199 Preparation of tert-butyl3-{4-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate

Intermediate AB (300 mg, 0.785 mmol) and Intermediate M (499 mg, 1.18mmol) were allowed to react using the procedure to make tert-butyl3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate.The product was purified using flash chromatography with 0-4%MeOH/CH₂Cl₂ as eluent to yield 271 mg (58%) pure desired product. ¹H-NMR(DMSO-d₆) δ 9.30(s, 1H), 8.94 (s, 1H), 8.63 (d, J=5.1, 1H), 7.91 (s,1H), 7.59 to 7.37 (m, 2H), 6.60(s, 1H), 3.75 (m, 2H), 3.45 (m, 3H), 2.40to 2.1 (m, 1H), 2.08 (m, 1H), 0.94 (s, 9H); MS [M+H]⁺=600.2; LCMSRT=3.27

Example 200 Preparation ofN-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a dry flask was added1-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(830 mg, 0.614 mmol) followed by a solution of 1:3 Trifluoroacetic acidin dichloromethane (8 mL). The mixture was stirred under N2 atmospherefor 3.5 h. The reaction was then partitioned between dichloromethane(150 mL) and 10% aqueous potassium carbonate. The aqueous layer was backextracted with dichloromethane (2×50 mL). The combined organic layer waswashed with brine (50 mL) then dried with Sodium Sulfate. The solventwas evaporated under reduced pressure to yield 485 mg (70%) of thedesired product. ¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (bs, 1H), 9.26 (bs,1H), 8.60 (d, J=2.4 Hz, H), 8.29 (t, 8.4 Hz, 1H), 7.93 (s, 1H),7.51-7.22 (m, 4H), 6.74 (s, 1H), 3.86 (m, 2H), 3.35-3.10 (m, 3H), 2.41(m, 1H), 2.15 (m, 1H); MS [M+H]⁺=518.3; HPLC RT=2.40.

Example 201 Preparation ofN-(4-{4-amino-7-[1-(methylsulfonyl)pyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 200 (70 mg, 0.135 mmol) was dissolved in anhydrous THF (2 mL).Methanesulfonyl chloride (16 uL, 0.135 mmol) was added to the reactionmixture followed by triethylamine (56 uL, 0.406 mmol). The suspensionwas stirred at rt overnight. The product was purified using flashchromatography with 0-6% (2N NH₃ in MeOH/CH₂Cl₂ as eluent to yield 71 mg(88%) pure desired product. ¹H NMR (300 MHz, DMSO-d₆) δ 9.41 (s, 1H),9.26 (s, 1H), 8.66 (m, 1H), 8.26 (t, J=8.4 Hz, 1H), 7.93 (s, 1H), 7.54to 7.22 (m, 4H), 6.74 (s, 1H), 3.88 to 3.74 (m, 2H), 3.88 to 3.30 (m,3H), 2.92 (m, 3H), 2.48 (m, 1H), 2.27 (m, 1H); MS [M+H]⁺=596.3; HPLCRT=2.98.

Example 202 Preparation ofN-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 200 (91 mg, 0.182 mmol) was dissolved in anhydrous THF (2 mL).Acetic anhydride (19 uL, 0.200 mmol) was added to the reaction mixturefollowed by triethylamine (76 uL, 0.542 mmol). The reation mixture wasstirred at room temperature for 3 hours. The product was purified usingether trituration to yield 44 mg (58%) pure desired product. ¹H NMR (300MHz, DMSO-d₆) δ 9.49 (bs, 1H), 9.34 (bs, 1H), 8.64 (dd, J=7.5 Hz, J=2.1Hz, 1H), 8.25 (t, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.54 to 7.22 (m, 5H),6.67 (d, J=15 Hz, 1H), 3.80 (m, 2H), 3.60 (m, 2H), 3.40 (m, 1H), 2.43 to2.10 (m, 2H), 1.96 (s, 3H); MS [M+H]⁺=560.2; HPLC RT=3.13.

Example 203 Preparation of3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N,N-dimethylpyrrolidine-1-carboxamide

Example 200 (70 mg, 0.135 mmol) was dissolved in anhydrous THF (2 mL)and dimethylcarbamic chloride (15 uL, 0.149 mmol) was added to thereaction mixture followed by triethylamine (63 uL, 0.406 mmol). Thereaction mixture was stirred at room temperature for overnight. Theproduct was purified using flash chromatography with 0-6% (2N NH₃ inMeOH)/CH₂Cl₂ as eluent to yield 46 mg (58%) pure desired product. ¹H NMR(300 MHz, DMSO-d₆) δ 9.43(s, 1H), 9.28 (s, 1H), 8.65 (m, 1H), 8.25 (t,J=8.4 Hz, 1H), 7.91 (s, 1H), 7.51 to 7.21 (m, 4H), 6.64 (s, 1H), 3.75(m, 2H), 3.45 to 3.29 (m, 3H), 2.73 (s, 6H), 2.25 (m, 1H), 2.00 (m, 1H);MS [M+H]⁺=589.2; HPLC RT=3.21.

Example 204 Preparation ofN-{4-[4-amino-7-(1-glycoloylpyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 200 (70 mg, 0.135 mmol) in DMF (1.5 mL) was added glycol acid(11 mg, 0.149 mmol), triethylamine (57 ul, 0.406 mmol), and (BOP)benzoltriazolyloxytris(dimethylamino)phosphomium-hexafluorophosphate (66mg, 0.149 mmol). The reaction was stirred at room temperature overnight.The mixture was partitioned between ethyl acetate (25 mL) and H2O (25mL). The layers were separated and the organic was washed with H2O (20mL). The combined aqueous layers were extracted with ethyl acetate (20mL). The combined organics were washed with water (5×20 mL) to removeDMF, dried (Na2SO4), and evaporated. The crude material was purified bytrituration with ether to yield 11 mg (14%) of the desired product. MS[M+H]⁺=576.2; HPLC RT=2.97.

Example 205 Preparation ofN-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Example 208 was deprotected using the procedure described in Example200. The crude intermediate was then treated under the proceduredescribed in Example 202 to provide the tide compound. ¹H NMR (300 MHz,DMSO-d₆) δ 10.12 (s, 1H), 10.05 (bs, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.26(t, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.39 to 7.23 (m, 3H),6.65 (d, J=4.5 Hz, 1H), 3.94 to 3.29 (m, 5H), 2.94 to 2.15 (m, 2H), 1.95(s, 3H); MS [M+H]⁺=543.2; HPLC RT=2.66.

Example 206 Preparation of1-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 199 was deprotected using the procedure described in Example200. ¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.56 (s, 1H), 7.88 (s,1H), 7.86 (s, 1H), 7.61 to 7.35 (m, 6H), 6.56 (s, 1H), 3.64 (m, 1H),3.59 (m, 1H), 3.22 (m, 1H), 2.93 (m, 1H,) 2.74 (m, 1H), 2.14 (m, 1H),1.83 (m, 1H), MS [M+H]⁺,=499.9; HPLC RT=2.33.

Example 207 Preparation of1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 206 (91 mg, 0.182 mmol) is allowed to react with aceticanhydride (20 mg, 0.200 mmol) following the procedure to makeN-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)-phenyl]urea.The product was purified by ether trituration to yield 25 mg (25%) puredesired product. ¹H NMR (300 MHz, DMSO-d₆) δ 10.12 (s, 1H), 10.05 (bs,1H), 8.54 (d, J=5.1 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92(s, 1H), 7.39 to 7.23 (m, 3H), 6.65 (d, J=4.5 Hz, 1H), 3.94 to 3.29 (m,5H), 2.94 to 2.15 (m, 2H), 1.95 (s, 3H); MS [M+H]⁺=543.2; HPLC RT=2.66.

Example 208 Preparation of tert-butyl3-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate

Intermediate AB (432 mg, 1.13 mmol) and1-[2-fluoro-4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea(600 mg, 1.41 mmol) were allowed to react using the procedure to makeExample 198. The product was purified using flash chromatography with0-6% (2N NH₃ in MeOH/CH₂Cl₂ as eluent to yield 149 mg (22%) pure desiredproduct. ¹H-NMR (DMSO-d₆) δ 10.12 (s, 1H), 10.05 (s, 1H), 8.54 (d, J=5.7Hz, 1H), 8.26 (t, J=8.7 Hz, 1H), 8.00 (s, 1H), 7.92 (s, 1H), 7.39 to7.23 (m, 3H), 6.65 (s, 1H), 3.75 (m, 2H), 3.48 to 3.30 (m, 3H), 2.27 (m,1H), 2.08 (m, 1H), 1.39 (s, 9H); MS [M+H]⁺=601.2; LCMS RT=3.27

Example 209 Preparation of4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-methylpiperidine-1-carboxamide

To a flask containing 3 ml of methylene chloride was added1-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(Example 111) (75 mg, 0.141 mmol, 1.0 eq). To this suspension was addedTHF dropwise until complete dissolution occurs. To this solution wasadded methyl isocyanate (8.8 μl, 0.148 mmol, 1.05 eq.) and reactionallowed to stir at room temperature for 17 h. Reaction solution wasconcentrated to dryness and residue dissolved in EtOAc. Wash 2× withsaturated sodium bicarbonate, 1× brine, layers separated, organics dried(Na₂SO₄), filtered, condensed and purified via flash chromatography (1:1THF:hexanes). The purified fractions collected and concentrated todryness. Residue was stirred in hexanes and filtered to obtain titlecompound (50 mg, 60.2% yield). ¹H-NMR (DMSO-d₆) δ 9.41 (d, J=2.8 Hz,1H), 9.25 (d, J=2.3 Hz, 1H), 8.65 (dd, J=7.5, 2.4 Hz, 1H), 8.25 (t,J=8.6 Hz, 1H), 7.90 (s, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.32 (dd,J=12.4, 2.0 Hz, 1H), 7.23 (dd, J=8.5, 1.4 Hz, 1H), 6.57 (s, 1H) 6.44 (q,J=4.3 Hz, 1H), 4.05 (d, J=13.3 Hz, 2H), 3.28 (m, 1H), 2.80 (t, J=12.2Hz, 2H), 2.56 (d, J=4.5 Hz, 3H), 1.95 (d, J=11.3 Hz, 2H), 1.52 (m, 2H);MS [M+H]⁺=589; LCMS RT=3.11 min.

Example 210 Preparation of4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N,N-dimethylpiperidine-1-carboxamide

To a flask containing 3 ml of methylene chloride was added1-[4-(4amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(Example 111) (75 mg, 0.141 mmol, 1.0 eq). To this suspension was addedTHF dropwise until complete dissolution occurs. To this solution wasadded dimethylcarbomoyl chloride (13.6 μl, 0.148 mmol, 1.05 eq.) andreaction allowed to stir at room temperature for 17 h. Reaction solutionwas concentrated to dryness and residue dissolved in EtOAc. Washed 2×with saturated sodium bicarbonate, 1× brine, layers were separated,organics dried (Na₂SO₄), filtered, condensed and purified via flashchromatography (1:1 THF:hex). The purified fractions collected andconcentrated to dryness. Residue was stirred in hexanes and filtered toobtain title compound (26 mg, 30.6% yield). ¹H-NMR (DMSO-d₆) 9.41 (d,J=2.6 Hz, 1H), 9.25 (d, J=2.6 Hz, 1H), 8.65 (dd, J=7.1, 2.5 Hz, 1H),8.26 (t, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.33(dd, J=12.3, 2.0 Hz, 1H), 7.23 (dd, J=8.6, 1.6 Hz, 1H), 6.59 (s, 1H),3.65 (d, J=13.2 Hz, 2H), 3.28 (m, 1H), 2.85 (t, J=12.3 Hz, 2H), 2.74 (s,6H), 1.99 (m, 2H), 1.52 (m, 2H) MS [M+H]⁺=603; LCMS RT=3.20 min.

Example 211N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol

To a solution of Intermediate B (195 mg, 0.91 mmol) in THF at −78° C.under N₂ was added dropwise n-butyllithium (1.46 ml, 3.66 mmol). Thereaction mixture was stirred for 15 min and then gaseous ethylene oxidewas bubbled into the reaction mixture for 5 min. The dry-ice bath wasremoved and warmed up to rt. Analytical HPLC found a new peak and thenthe reaction was quenched with 2 ml saturated aq NH₄Cl followed byaddition of 10 ml EtOAc and H₂O (2 ml). The organic phase was collectedand washed with brine and dried over Na₂SO₄ and evaporated to crude asyellow oil. The crude was dissolved in 5 ml 10% MeOH/CH₂Cl₂ and 4 mlsilica gel was added and then solvent evaporated. The crude in thesilica gel was loaded on an MPLC column and was eluted with a gradient0-10% MeOH in CH₂Cl₂ to give 20 mg of the desired product. MS[M+H]⁺=178.9; LCMS RT=1.1 min

Step 2: Preparation of7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol(440 mg, 2.5 mmol) in THF (10 ml) and CH₂Cl₂ anhydrous (10 ml) and wasadded SOCl₂ (0.36 ml, 4.9 mmol) and stirred at rt. After 20 min allstarting material was consumed. The crude reaction mixture wasconcentrated in vacuo to dryness and was suspended in dry CH₂Cl₂. Thesolvent was evaporated and the crude was re-suspended in CH₂Cl₂ andconcentrated in vacuo to dryness. The resulting solid was dissolved inDMF (10 ml) and was added triethylamine (0.97 ml, 7.2 mmol), morpholine(1.0 ml, 11.7 mmol) and NaI (280 mg, 1.87 mmol) and heated at 55° C. 24h. Cooled to rt, the reaction crude was diluted with EtOAc (30 ml) andwashed with H₂O (2×) and brine (2×), dried over Na₂SO₄ and concentratedto give yellow solid. The crude was purified by MPLC with 0-10%MeOH/CH₂Cl₂ to give 149 mg of the titled compound (yield 25%). MS[M+H]⁺=248; LCMS RT=1.05 min.

Step 3: Preparation of5-bromo-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a solution of7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (149 mg,0.6 mmol) in DMF (3 ml) at −20 C was added1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (69 mg, 0.24 mmol) inthree portions. The reaction was stirred at −20 C for 3 h. Upon thecompletion, the reaction was quenched with aqueous saturated Na₂SO₃ andallowed to warm up to rt. The crude was extracted with ethyl acetate.The organic layer was collected and washed with brine, dried over Na₂SO₄and concentrated. The resulting crude was purified via columnchromatography (95:5 v/v CH₂Cl₂—CH₃OH) to afford 75 mg of the titlecompound as yellow solid (yield 39%). MS [M+H]⁺=326.2; LCMS RT=1.15 min.

Step 4: Preparation of Title Compound

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting5-bromo-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,23]triazine-4-aminefor Intermediate V and Intermediate AH for(N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea.¹H-NMR (DMSO-d₆) δ 9.45 (dd, J=15, 3 Hz, 2H), 8.65-8.61 (m, 1H),8.17-8.11 (m, 1H), 7.85(s, 1H), 7.53-7.43(m, 2H), 6.58(s, 1H), 3.56(t,J=5 Hz, 4H), 3.05 (t, J=4 Hz, 2H), 2.63(t, J=8 Hz, 2H), 2.46-2.43(m,4H); MS [M+H]⁺=580.2; LCMS RT=2.67 min.

Example 212N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of2-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol

To a solution of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol(777 mg, 4.3 mmol) in DMF (22 mL) at −20° C. (IPA and dry ice) was added1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (359 mg, 1.72 mmol) )was added in 4 portions within 20 min. The reaction was stirred at −20°C. for 30 min. Analytical HPLC indicated 22% starting material remanded,additional B (90 mg, 0.30 mmol) was added and stirred for 20 min. Thereaction was quenched with satd. Na₂SO₃ and warmed up to rt. The crudewas extracted w/EtOAc 5×. The organic was washed with 5% aq K₂CO₃ andbrine. Dried over Na₂SO₄ and concentrated. The crude was purified byMPLC with 0-7% MeOH/CH₂Cl₂ to give 814 mg of desired product (yield,72.6%). MS [M+H]⁺=257.3; LCMS RT=1.14 min.

Step 2: Preparation of1-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A mixture of 2-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol(750 mg, 2.9 mmol) and Intermediate O (1.55 g, 3.5 mmol) and 1M Na₂CO₃in 1,4-dioxane (32 ml) was degassed and added Pd(PPh₃)₄ then was heatedat 80° C. for 16 h. Cooled to rt, diluted with EtOAc and washed withsat'd NaHCO₃ and dried (Na₂SO₄) and concentrated. The crude was purifiedby MPLC with 5% MeOH/CH₂Cl₂ to afford 1.2 g of the titled compound(yield, 89%). MS [M+H]⁺=493.3; LCMS RT=2.84 min.

Step 3: Preparation of1-{4-[4-amino-7-(2-bromoethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a suspension of1-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(1.28 g, 2.60 mmol) in anhyrous THF (32 ml) at 0° C. was added CBr₄(1.03 g, 3.1 mmol)) followed by Ph₃P (0.75 g, 2.9 mmol) and the reactionwas stirred at rt for 24 h. The reaction mixture was poured into H₂O(100 ml) and extracted with 150 ml EtOAc. The organic layer was washedwith satd. aq NaHCO₃, brine and dried over Na₂SO₄ and was concentratedto give a yellow oil (1.6 g), which was used without furtherpurification. MS [M+H]⁺=557.2; LCMS RT=3.27 min.

Step 4: Preparation of the Title Compound

A mixture of the crude1-{4-[4-amino-7-(2-bromoethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(500 mg, crude, 0.331 mmol), morpholine (0.10 ml, 1.12 mmol),triethylamine (0.08 ml, 0.60 mmol) and sodium iodide (7 mg, 0.05 mmol)in 4 ml DMF was heated at 55° C. in a closed vial for 16 h. Cooled tort, the crude was diluted with 20 ml EtOAc and was washed with aqsaturated NaHCO₃, brine and dried over Na₂SO₄. The crude wasconcentrated and purified via column chromatography (95:5 v/vCH₂Cl₂—CH₃OH) to afford 64 mg of the title compound (yield 47%). ¹H-NMR(DMSO-d₆ and 1 drop TFA-d) δ 9.44 (d, J=3 Hz, 1H), 9.33(d, J=3 Hz, 1H),8.65(dd, J=7, 2 Hz, 1H, 8.32(t, J=8 Hz, 1H), 8.15(s, 1H), 7.55-7.51(m,1H), 7.48-7.24(m, 4H), 6.83(s, 1H), 4.03-4.01 (m, 2H), 3.69-3.49(m, 8H),3.38-3.33(m, 2H); MS [M+H]⁺=562.3; LCMS RT=2.84 min.

Example 213N-(4-{4-amino-7-[2-(dimethylamino)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 212 was used toprepare the title compound by substituting diethylamine for morpholinein step 4. ¹H-NMR (CD₃OD) δ 8.65 (d, J=8 Hz, 1H), 8.25 (t, J=8 Hz, 1H),7.83(s, 1H), 7.36-7.25(m, 4H), 6.61(s, 1H), 3.20(t, J=7 Hz, 2H),2.86-2.81(m, 2H), 2.40(s, 6H); MS [M+H]⁺=520.3; LCMS RT=2.42 min.

Example 214N-(4-{4-amino-7-[2-(4-methylpiperazin-1-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 212 was used toprepare the title compound by substituting 1-methylpiperazine formorpholine in step 4. ¹H-NMR (DMSO-d₆) δ 9.42 (d, J=2 Hz, 1H), 9.26 (d,J=2 Hz, 1H), 8.65 (dd, J=8, 2 Hz, 1H), 8.26(t, J=9 Hz, 1H), 7.89(s, 1H),7.43-7.20(m, 3H), 6.61(s, 1H), 3.05(m, 2H), 2.68-2.58(m, 4H),2.43-2.40(m, 3H); MS [M+H]⁺=575.2; LCMS RT=2.39 min.

Example 215N-[4-(4-amino-7-{2-[2-(methoxymethyl)pyrrolidin-1-yl]ethyl}pyrrolo-[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 212 was used toprepare the title compound by substituting(2S)-2-(methoxymethyl)pyrrolidine for morpholine in step 4. ¹H-NMR(CD₃OD) δ 9.64 (d, J=9 Hz, 1H), 8.24 (t, J=9 Hz, 1H), 7.82 (s, 1H),7.35-7.24(m, 4H), 6.58(s, 1H), 3.63-3.43(m, 3H), 3.19-3.16(m, 2H),2.83-2.73(brd, 2H), 2.47-2.44(m, 2H), 2.0-1.94(m, 1H), 1.64-1.58(m, 1H);MS [M+H]⁺=590.3; LCMS RT=2.51 min.

Example 216N-{4-[4-amino-7-(2-pyrrolidin-1-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 212 was used toprepare the title compound by substituting pyrrolidine for morpholine instep 4. ¹H-NMR (DMSO-d₆) δ 9.40(d, J=3 Hz, 1H), 9.25 (t, J=2 Hz, 1H),8.65(dd, J=8, 2 Hz, 1H), 8.26(t, J=8 Hz, 1H), 7.89(s, 1H), 7.51(t, J=10Hz, 1H), 7.42-7.40(m, 1H), 7.30(dd, J=10, 2 Hz, 1H), 7.22(dd, J=8, 2 Hz,1H), 6.61(s, 1H), 3.05(t, J=8 Hz, 2H), 2.82-2.77(m, 2H), 2.54-2.51(m,4H), 1.68-1.65(m, 4H); MS [M+H]⁺=546.3; LCMS RT=2.47 min.

Example 217N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting Intermediate AJ forintermediate M. ¹H-NMR (DMSO-d₆ and 1 drop TFA-d) δ 9.69(d, J=2 Hz, 1H),9.19(s, 1H), 8.62(d, J=2 Hz, 1H), 8.27(t, J=8 Hz, 1H), 8.00(d, J=2 Hz,1H), 7.74(d, J=8 Hz, 1H), 7.41-7.23(m, 3H), 6.73(s, 1H), 3.97-3.41(m,5H), 3.25-2.95(m, 7H), 2.48-2.25(m, 2H); MS [M+H]⁺=592.2; LCMS RT=2.65min.

Example 218N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting Intermediate AI forintermediate M. ¹H-NMR (DMSO-d₆) δ 9.16 (d, J=2 Hz, 1H), 9.05 (d, J=2Hz, 1H), 8.29 (t, J=8 Hz, 1H), 8.04 (dd, J=8, 2 Hz, 1H), 7.91(s, 1H),7.35-7.31(m, 3H), 6.86-6.82(m, 1H), 6.60(s, 1H), 3.58 (t, J=4 Hz, 4H),2.91(t, J=8 Hz, 2H), 2.45-2.30(m, 9H), 1.9-1.77 (m, 2H); MS[M+H]⁺=576.7; LCMS RT=2.57 min.

Example 219N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 232, using acetic anhydride inplace of methanesulfonyl chloride 34 mg (63%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.74 (d, J=2.7 Hz, 1H), 9.01 (s, 1H), 8.65(dd, J=2.1, 7.2 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.92 (s, 1H), 7.54-7.48(m, 2H), 7.42-7.35 (m, 2H), 6.61 (s, 1H), 4.51-4.46 (m, 1H), 3.93-3.89(m, 1H), 3.45-3.14 (m, 5H), 2.03 (s, 3H), 1.67-1.46 (m, 2H); MS[M+H]⁺=590.3, 592.2; LCMS RT=2.98 min.

Example 220N-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting2-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol forIntermediate V and substituting Intermediate O for intermediate M.¹H-NMR (DMSO-d₆) δ 9.41 (dd, J=3 Hz, 1H), 9.24(d, J=3 Hz, 1H),8.67-8.63(dd, J=8, 3 Hz, 1H), 8.26(t, J=9 Hz, 1H), 7.89(s, 1H),7.54-7.47(m, 1H), 7.43-7.7.20(m, 3H), 6.60(s, 1H), 4.76(t, J=5 Hz, 1H),3.73 (t, J=5 Hz, 2H), 3.03 (t, J=7 Hz, 2H); MS [M+H]⁺=493.2; LCMSRT=2.70 min.

Example 221N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 108 was used toprepare the title compound by substituting Intermediate AF forintermediate M. ¹H-NMR (DMSO-d₆) δ9.37 (d, J=2 Hz, 1H), 8.66(dd, J=8, 2Hz, 1H), 8.55(d, J=2 Hz, 1H), 7.98(d, J=2 Hz, 1H), 7.87(s, 1H),7.54-7.47(m, 1H), 7.39-7.36(m, 1H), 7.28(d, J=2 Hz, 1H), 7.24(dd, J=8, 2Hz, 1H), 6.52(s, 1H), 3.56-3.54(m, 4H), 2.88(t, J=5 Hz, 2H),2.36-2.30(m, 9H), 1.89-1.81(m, 2H); MS [M+H]⁺=572.2; LCMS RT=2.50 min.

Example 222N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea

The procedure used for the preparation Example 108 was used to preparethe title compound by substituting1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-(3-methylphenyl)ureafor intermediate M. ¹H-NMR (DMSO-d₆) δ 9.01 (s, 1H), 8.61 (d, J=3 Hz,1H), 8.24 (t, J=8 Hz, 1H), 7.88 (s, 1H), 7.31-7.13 (m, 4H), 6.80(d, J=7Hz, 1H), 6.56(s, 1H), 3.54(t, J=4 Hz, 4H), 2.87(t, J=8 Hz, 2H),2.36-2.27(m, 9H), 1.86-1.81(m, 2H); MS [M+H]⁺=504.2; LCMS RT=2.26 min.

Example 223N-{4-[4amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation Example 108 was used to preparethe title compound by substituting Intermediate Q for intermediate M.¹H-NMR (DMSO-d₆) δ 9.44(s, 1H), 8.74(d, J=2 Hz, 1H), 8.20(t, J=8 Hz,1H), 8.05(s, 1H), 7.88(s, 1H), 7.54-7.52(m, 2H), 7.35-7.20(m, 3H),6.57(s, 1H), 3.54(t, J=4 Hz, 3H), 3.32(m, 5H), 2.87(t, J=7 Hz, 2H),2.47-2.32(m, 4H), 1.86-1.81(m, 2H); MS [M+H]⁺=558.2; LCMS RT=2.39 min.

Example 224N-{4-[4-amino-7-(4-morpholin-4-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of7-((1E)-4-[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a stirred suspension of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine(5.0 g, 23.5 mmol),trans-1-buten-1-yl-(4-tert-butylsimethylsiloxy-4′,4′,5′,5′-tetramethyl-(1′,3′,2′)-dioxaborolane(14.6 g, 46.9 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1.72 g, 2.35 mmol) indegassed DME (175 mL) was added aqueous Na₂CO₃ solution (2 M, 35.2 mL).The reaction was heated (80° C.) for 17 h and then cooled to rt. Themixture was partitioned between ethyl acetate (200 mL) and water (200mL) and the layers were separated. The organic phase was further washedwith water (200 mL), brine, dried (Na₂SO₄), and concentrated. The crudematerial was purified by MPLC chromatography using a gradient of 50 to75% ethyl acetate in hexanes to afford 5.35 g (72%) of the desiredproduct as a pale yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.76 (s,1H), 7.59 (br s, 2H), 6.81-6.78 (m, 1H), 6.76-6.67 (m, 2H), 6.38-6.29(m, 1H), 3.65 (t, 2H), 2.35 (q, 2H), 0.82 (s, 9H) 0.00 (s, 6H); ES-MSm/z 319.3 [M+H]⁺, HPLC RT (min) 3.01.

Step 2: Preparation of7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a dry flask purged with N₂ was added platinum(IV) oxide (635 mg, 2.80mmol) followed by7-((1E)-4-{[tert-butyl(dimethyl)silyl]oxy}but-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(6.35 g, 19.9 mmol) as a solution in acetic acid (100 mL). The mixturewas stirred under an H₂ atmosphere for 16 h. The mixture was filteredthrough a pad of Celite® rinsing with acetic acid. The solvent wasevaporated under reduced pressure and the residue was made basic withsaturated aqueous NaHCO₃ solution. The resulting solid was collected byfiltration and dried in vacuo to afford 5.6 g (88%) of the desiredproduct. ¹H NMR (300 MHz, DMSO-d₆) δ 7.76 (s, 1H), 7.52 (br s, 2H), 6.77(d, 1H), 6.38 (d, 2H), 3.57 (t, 2H), 2.82 (t, 2H), 1.74-1.62 (m, 2H),1.54-1.43(m, 2H), 0.83 (s, 9H), 0.00 (s, 6H); ES-MS m/z 321.2 [M+H]⁺,HPLC RT (min) 3.11.

Step 3: Preparation of5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

To a cooled (−20° C.) solution of7-(4-{[tert-butyl(dimethyl)silyl]oxy)butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(5.60 g, 17.5 mmol) in tetrahydrofuran (85 mL) was added1,3-dibromo-5,5-dimethylhydantoin (2.50 g, 8.74 mmol) in four portionsover 15 min. The mixture was allowed to stir (−20° C.) for 2 h. Thereaction was quenched with the addition saturated aqueous Na₂SO₃solution and was allowed to warm to rt. The mixture was extracted withethyl acetate (3×75 mL). The combined organics were washed with brine,dried (Na₂SO₄) and concentrated to dryness. The crude material waspurified by MPLC chromatography using a gradient of 50% to 75% ethylacetate in hexanes to afford 6.29 g (90%) of the desired product. ¹H NMR(300 MHz, DMSO-d₆) δ 7.80 (s, 1H), 6.58 (s, 1H), 3.56 (t, 2H), 2.81 (t,2H), 1.72-1.61 (m, 2H), 1.51-1.42 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H);ES-MS m/z 399.2 [M+H]⁺, HPLC RT (min) 3.72.

Step 4: Preparation of1-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 7 was used to preparethe title compound by substituting5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminefor(5-bromo-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amineand Intermediate O for Intermediate R. MS [M+H]⁺=635.0; LC/MS RT=4.04min.

Step 5:1-{4-[4-amino-7-(4-hydroxybutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2fluoro-5-(trifluoromethyl)phenyl]urea

To a suspension of1-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)-phenyl]ureain 3 ml 95:5 EtOH/H₂O was added 30 μL conc. HCl. for 30 min. Thereaction mixture was quenched with 5 ml saturated NaHCO₃. After thesolvent EtOH was evaporated, the crude was extracted with EtOAc (3×).The resulting crude organic was dried and concentrated and trituatedwith EtOAc and hexane to give 115 mg of pure title compound as a whitesolid. MS [M+H]⁺=521.2; LC/MS RT=2.94 min.

Step 6: Preparation of1-{4-[4-amino-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 212 Step 3 was used toprepare the title compound by substituting1-{4-[4-amino-7-(4-hydroxybutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]ureafor1-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea.MS [M+H]⁺=583.2; LC/MS RT=3.50 min.

Step 7: Preparation of Title Compound

The procedure used for the preparation of Experiment 212 Step 4 was usedto prepare the title compound by substituting1-{4-[4-amino-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]ureafor1-{4-[4-amino-7-(2-bromoethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea.¹H-NMR (DMSO-d₆) δ 9.40(d, J=3 Hz, 1H), 9.24 (t, J=3 Hz, 1H) 6.65(dd,J=8, 3 Hz, 1H), 8.25(t, J=8 Hz, 1H), 7.89(s, 1H), 7.54-7.39(m, 2H),7.33(dd, J=4, 2 Hz, 1H), 7.24-7.21(m, 1H), 6.56(s, 1H), 3.53(t, J=5 Hz,4H), 2.87(t, J=2 Hz, 2H), 2.31-2.25(m, 6H), 1.72-1.52(m, 4H); MS[M+H]⁺=590.2; LCMS RT=2.46 min.

Example 225N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation Example 108 was used to preparethe title compound by substituting Intermediate AV for intermediate M.¹H-NMR (CD₃OD) δ 8.64(d, J=8 Hz, 1H), 8.24(d, J=8 Hz, 1H), 7.82(s, 1H),7.55(d, J=2 Hz, 1H), 7.43-7.33(m, 3H), 6.58(s, 1H), 3.69(t, J=5 Hz, 4H),2.52-2.47 (m, 6H), 2.02-1.97(m, 2H), MS [M+H]⁺=592.2; LCMS RT=2.60 min.

Example 226N-(4-{4-amino-7-[2-(1,4-oxazepan-4-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 212 was used toprepare the title compound by substituting 1,4-oxazepane for morpholinein step 4. ¹H-NMR (Acetone-d₆) δ 8.84 (t, J=2 Hz, 1H), 8.68 (brd, 1H),8.44-8.38 (m, 1H), 7.87 (s, 1H), 7.44-7.41(m, 2H), 7.31-7.29 (m, 2H),6.64 (s, 1H), 3.73-3.63 (m, 4H), 3.14 (dd, J=8, 7 Hz, 2H), 2.92 (dd,J=8, 7 Hz, 2H), 2.80-2.75 (m, 6H); MS [M+H]⁺=576.2; LCMS RT=2.91 min.

Example 227N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 162 was used toprepare the title compound by substituting Intermediate AJ forIntermediate Q and by substituting 1,4-dioxane for toluene as solvent.¹H-NMR (DMSO-d₆) δ 9.62(d, J=2 Hz, 1H), 9.13(s, 1H), 8.64(d, J=2 Hz,1H), 8.25(t, J=8 Hz, 1H), 7.92(s, 1H), 7.72(d, J=8 Hz, 1H), 7.41-7.23(m,3H), 6.71(s, 1H), 3.91(s, 2H), 3.16-3.11(m, 2H), 2.99(s, 2H), 2.61(t,J=6 Hz, 1H); MS [M+H]⁺=576.8; LCMS RT=2.58 min.

Example 228N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea

The procedure used for the preparation of Example 211 was used toprepare the title compound by substituting, in step 4, Intermediate AEfor Intermediate AH and by substituting 1,4-dioxane for toluene assolvent. ¹H-NMR (DMSO-d₆) δ 9.79(s, 1H), 8.31(t, J=8 Hz, 1H), 8.16(dd,J=5, 1 Hz, 1H), 7.89(s, 1H), 7.389s, 1H), 7.33-7.20(m, 2H), 7.08(dd,J=5, 2 Hz, 1H), 6.61(s, 1H), 3.59(t, J=4 Hz, 4H), 3.04(t, J=7 Hz, 2H),2.63(t, J=7 Hz, 2H), 2.43(m, 4H), 1.25(s, 9H); MS [M+H]⁺=533.1; LCMSRT=2.38 min.

Example 229N-{4-[4-amino-7-(1-lactoylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a stirring solution of DMF (1.0 mL) and Example 267 (50 mg, 0.091mmol), was added sodium 2-hydroxypropanoate (11 mg, 0.100 mmol),benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (42mg, 0.094 mmol), and triethylamine (32 μL, 0.228 mmol). The solution wasstirred at rt for 20 min, then concentrated under reduced pressure,diluted with EtOAc (20 mL), and washed with Na₂CO₃ (10 mL) followed bycitrate buffer (5 mL, pH 3-4) and brine (5 mL). The organic phase wasdried (Na₂SO₄) and concentrated to dryness. Trituration with 10%EtOAc/Hex afforded 25 mg (45%) of the desired compound. ¹H-NMR (DMSO-d₆)δ 9.74 (d, J=2.4 Hz, 1H), 9.01 (s, 1H), 8.65 (dd, J=2.1, 7.5 Hz, 1H),8.25 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 7.54-7.48 (m, 2H), 7.40-7.36 (m,2H), 6.64 (d, J=7.2 Hz, 1H), 4.48-4.44 (m, 2H), 4.07-4.00 (m, 1H),3.45-3.37 (2H), 3.21-3.12 (m, 1H), 2.81-2.66 (m, 2H), 2.05-2.01 (m, 2H),1.69-1.48 (m, 2H), 1.21-1.13 (m, 2H); MS [M+H]⁺=620.3, 622.2; LCMSRT=2.96 min.

Example 230N-(4-{4-amino-7-[1-(cyclopropylcarbonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, usingcyclopropanecarboxylic acid in place of sodium 2-hydroxypropanoate, 33mg (59%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.73(d, J=2.7 Hz, 1H), 9.01 (s, 1H), 8.65 (dd, J=2.4, 7.5 Hz, 1H), 8.24 (d,J=8.7 Hz, 1H), 7.91 (s, 1H), 7.54-7.48 (m, 2H), 7.43-7.36 (m, 2H), 6.62(s, 1H), 4.52-4.35 (m, 2H), 3.49-3.36 (m, 1H), 3.26-3.22 (m, 1H),2.87-2.55 (m, 2H), 2.10-2.00 (m, 2H), 1.67-1.42 (m, 2H), 0.86-0.65 (m,4H); MS [M+H]⁺=616.3, 618.2; LCMS RT=3.17 min.

Example 231N-(4-{4-amino-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-3-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using morpholin-4-ylaceticacid in place of sodium 2-hydroxypropanoate, 32 mg (52%) of the desiredproduct was isolated. ¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.7 Hz, 1H), 9.01(s, 1H), 8.65 (dd, J=2.7, 6.9 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.91 (s,1H), 7.55-7.48 (m, 2H), 7.44-7.36 (m, 2H), 6.59 (s, 1H), 4.49-4.44 (m,1H), 4.20-4.10 (m, 1H), 3.58-3.56 (m, 4H), 3.40-3.38 (m, 1H), 3.24-3.03(m, 2H), 2.71-2.68 (m, 1H), 2.39-2.42 (m, 4H), 2.22-2.20 (m, 1H),2.06-1.99 (m, 2H), 1.70-1.62 (m, 1H), 1.60-1.42 (m, 1H); MS[M+H]⁺=675.3, 677.2; LCMS RT=2.56 min.

Example 232N-(4-{4-amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a stirred solution of DMF (1.0 mL) and Example 267 (50 mg, 0.091mmol) at 0° C., was added triethylamine (32 μL, 0.228 mmol) followed bymethanesulfonyl chloride (11 mg, 0.092 mmol). The solution was stirredwhile warming to rt for 30 min, then concentrated under reducedpressure, diluted with EtOAc (20 mL), and washed with Na₂CO₃ (10 mL) andbrine (5 mL). The organic phase was dried (Na₂SO₄) and concentrated todryness. Trituration with Et₂O afforded 26 mg (45%) of the desiredcompound. ¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.7 Hz, 1H), 9.01 (s, 1H), 8.65(dd, J=2.4, 7.2 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.55-7.48(m, 2H), 7.44-7.36 (m, 2H), 6.65 (s, 1H), 3.68-3.64 (m, 2H), 3.31-3.24(m, 2H), 2.93-2.85 (m, 1H), 2.90 (s, 3H), 2.16-2.09 (m, 2H), 1.76-1.71(m, 2H); MS [M+H]⁺=626.3, 628.2; LCMS RT=3.30 min.

Example 233N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using Example 275 in placeof Example 267, and glycolic acid in place of sodium2-hydroxypropanoate, 101 mg (22%) of the desired product was isolated.¹H-NMR (DMSO-d₆) δ 9.47 (s, 1H), 9.42 (s, 1H), 8.63 (dd, J=1.8, 7.2 Hz,1H), 8.17-8.11 (m, 1H), 7.90 (s, 1H), 7.55-7.48 (m, 1H), 7.44-7.39 (m,1H), 7.32-7.26 (s, 1H), 6.52 (s, 1H), 4.51-4.43 (m, 1H), 4.11-4.07 (m,2H), 3.78-3.74 (m, 1H), 3.43-3.32 (m, 1H), 3.15-3.12 (m, 1H), 2.76-2.71(m, 1H), 2.04-1.97 (m, 2H), 1.65-1.48 (m, 2H); MS [M+H]⁺=608.3; LCMSRT=3.03 min.

Example 234N-[4-(4-amino-7-glycoloylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a stirred solution of Example 256 (337 mg, 0.615 mmol), in MeOH (5mL), was added crushed anhydrous K₂CO₃ (250 mg, 1.81 mmol). The slurrywas allowed to stir for 20 min and partitioned between EtOAc (50 mL) andsaturated aq Na₂CO₃ (20 mL). The organic phase was washed with brine (10mL), dried (Na₂SO₄) and concentrated under reduced pressure. Triturationwith Et₂O afforded 18 mg (6%) of the desired product. ¹H-NMR (DMSO-d₆) δ9.60-9.39 (m, 2H), 8.65 (dd, J=2.1, 7.2 Hz, 1H), 8.24 (t, J=8.4 Hz, 1H),7.90 (s, 1H), 7.53-7.47 (m, 1H), 7.42-7.37 (m, 1H), 7.31 (dd, J=2.1, 12Hz, 1H), 7.21 (d, J=9.6 Hz, 1H), 6.87 (s, 1H), 2.60-2.51 (m, 2H); MS[M+H]⁺=507.1; LCMS RT=3.28 min.

Example 235N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

To a stirred solution of Example 271 (100 mg, 0.19 mmol) in ethanol (1mL) with freshly activated powdered 3 Å molecular seives, was addedacetic acid (195 μL, 1.94 mmol), sodium cyanoborohydride (34 mg, 0.78mmol) and [(1-methoxycyclopropyl)oxy](trimethyl)silane (233 μL, 1.17mmol). The reaction was heated to 60° C. and allowed to stir for 2 h.The mixture was allowed to cool and partitioned between EtOAc (40 mL)and 1N NaOH (20 mL). The organic phase was washed with brine (10 mL),dried (Na₂SO₄) and concentrated under reduced pressure. Trituration withEt₂O afforded 22 mg (20%) of the desired product. ¹H-NMR (DMSO-d₆) δ10.07 (s, 1H), 9.99 (br s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.20 (t, J=8.7Hz, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.34-7.25 (m, 2H), 7.18 (d, J=8.7Hz, 1H), 6.47 (s, 1H), 3.01-2.92 (m, 2H), 2.30-2.20 (m, 2H), 1.95-1.85(m, 2H), 1.76-1.50 (m, 2H), 1.31-1.25 (m, 2H), 0.85-1.75 (m, 1H),0.40-0.30 (m, 1H), 0.30-0.21 (m, 1H), 0.05-0.00 (m, 1H); MS[M+H]⁺=555.2; LCMS RT=2.80 min.

Example 236N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using Example 271 in placeof Example 267, and glycolic acid in place of sodium2-hydroxypropanoate, 36 mg (17%) of the desired product was isolated.¹H-NMR (DMSO-d₆) δ 10.13 (s, 1H), 10.06 (br s, 1H), 8.54 (d, J=5.1 Hz,1H), 8.27 (t, J=8.7 Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.39-7.32 (m,2H), 7.24 (d, J=8.4 Hz, 1H), 6.60 (s, 1H), 4.48-4.36 (m, 1H), 4.11 (d,J=2.7 Hz, 2H), 3.81-3.75 (m, 1H), 3.47-3.34 (m, 1H), 3.18-3.12 (m, 1H),2.78-2.66 (m, 1H), 2.05-1.97 (m, 2H), 1.66-1.54 (m, 2H); MS[M+H]⁺=573.2; LCMS RT=2.98 min.

Example 237N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 232, using Example 271 in placeof Example 267, and acetic anhydride in place of methanesulfonylchloride, 45 mg (69%) of the desired product was isolated. ¹H-NMR(DMSO-d₆) δ 10.14 (s, 1H), 10.07 (br s, 1H), 8.54 (d, J=5.4 Hz, 1H),8.27 (t, J=8.7 Hz, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.39-7.32 (m, 2H),7.26 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 4.51-4.47 (m, 1H), 3.94-3.89 (m,1H), 3.75-3.65 (m, 1H), 3.24-3.15 (m, 1H), 2.71 (s, 3H), 2.67-2.65 (m,1H), 2.03-21.97 (m, 2H), 1.69-1.46 (m, 2H); MS [M+H]⁺=557.2; LCMSRT=3.08 min.

Example 238N-(4-{4-amino-7-[1-(cyclopropylcarbonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using Example 271 in placeof Example 267, and cyclopropanecarboxylic acid in place of sodium2-hydroxypropanoate, 42 mg (62%) of the desired product was isolated.¹H-NMR (DMSO-d₆) δ 10.13 (s, 1H), 10.05 (br s, 1H), 8.54 (d, J=5.4 Hz,1H), 8.26 (t, J=8.7 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39-7.32 (m,2H), 7.26 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 4.51-4.32 (m, 2H), 3.49-3.35(m, 1H), 3.10-2.90 (m, 3H), 2.07-1.97 (m, 2H), 1.70-1.40 (m, 2H), 1.12(t, J=7.2 H, 2H), 0.72-0.67 (m, 2H); MS [M+H]⁺=583.2; LCMS RT=3.10 min.

Example 239N-(4-{4-amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 232, using Example 271 in placeof Example 267, 18 mg (26%) of the desired product was isolated. ¹H-NMR(DMSO-d₆) δ 10.13 (s, 1H), 10.05 (br s, 1H), 8.54 (d, J=5.1 Hz, 1H),8.27 (t, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.39-7.32 (m, 2H),7.25 (dd, J=1.8 Hz, 1H), 6.63 (s, 1H), 3.68-3.64 (m, 1H), 3.32-3.24 (m,2H), 2.89 (s, 3H), 2.13-2.07 (m, 2H), 1.76-1.70 (m, 2H), 1.25-1.20 (m,2H); MS [M+H]⁺=593.2; LCMS RT=3.10 min.

Example 240N-(4-{4-amino-7-[1-(N,N-dimethylglycyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using N,N-dimethylglycinehydrochloride in place of sodium 2-hydroxypropanoate, 23 mg (20%) of thedesired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.7 Hz, 1H),9.01 (s, 1H), 8.65 (dd, J=1.8, 7.5 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.91(s, 1H), 7.53-7.48 (m, 2H), 7.44-7.36 (m, 2H), 6.59 (s, 1H), 4.49-4.44(m, 1H), 4.144.09 (m, 1H), 3.50-3.30 (m, 1H), 3.22-3.11 (m, 3H),2.72-2.71 (m, 1H), 2.24 (s, 6H), 2.05-2.01 (m, 2H), 1.70-1.42 (m, 2H);MS [M+H]⁺=633.2, 635.2; LCMS RS=2.54 mi.

Example 241N-(4-{4-amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a stirred solution of Example 267 (50 mg, 0.091 mmol) in NMP (1 mL),was added triethylamine (24 μL, 0.18 mmol) and 1-bromo-2-methoxyethane(10 μL, 0.10 mmol). The reaction was heated to 60° C. and allowed tostir for 17 hr. The mixture was allowed to cool and partitioned betweenEtOAc (30 mL) and saturated aq NaHCO₃ (15 mL). The organic phase waswashed with brine (10 mL), dried (Na₂SO₄) and concentrated to dryness.Trituration with Et₂O afforded 13 mg (24%) of the desired product.¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.4 Hz, 1H), 9.01 (s, 1H), 8.65 (dd,J=2.1, 7.2 Hz, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.91 (s, 1H), 7.55-7.49 (m,2H), 7.44-7.36 (m, 2H), 6.60 (s, 1H), 3.38-3.26 (m, 7H), 2.67 (s, 3H),2.19-2.14 (m, 3H), 1.93-1.83 (m, 3H); MS [M+H]⁺=606.4, 608.3; LCMSRT=2.99 min.

Example 242N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 111, using Example 272 in placeof Example 110, 400 mg (96%) of the desired product was isolated. ¹H-NMR(DMSO-d₆) δ 9.47-9.40 (m, 1H), 9.02-8.99 (m, 1H), 8.62 (dd, J=2.1, 6.9Hz, 1H), 7.89 (s, 1H), 7.59-7.46 (m, 3H), 7.40-7.36 (m, 3H), 6.51 (s,1H), 3.32-3.29 (m, 1H), 3.27-3.17 (m, 2H), 2.89-2.81 (m, 2H), 2.07-2.03(m, 2H), 1.75-1.66 (m, 2H); MS [M+H]⁺=514; LCMS RT=2.74 min.

Example 243N-(4-{4-amino-7-[1-(2-ethoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 241, using1-bromo-2-ethoxyethane in place of 1-bromo-2-methoxyethane, 29 mg (51%)of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.7Hz, 1H), 9.00 (s, 1H), 8.65 (dd, J=2.1, 7.5 Hz, 1H), 8.24 (d, J=8.4 Hz,1H), 7.89 (s, 1H), 7.55-7.49 (m, 2H), 7.44-7.36 (m, 2H), 6.59 (s, 1H),3.47 (t, J=6.3 Hz, 2H), 3.28 (t, J=6.9 Hz, 3H), 3.10-2.95 (m, 3H),2.19-2.09 (m, 4H), 1.93-1.83 (m, 4H), 1.75-1.60 (m, 2H); MS[M+H]⁺=620.4, 622.3; LCMS RT=2.97 min.

Example 244N-(4-{4-amino-7-[1-(2-ethoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 241, using Example 242 in placeof Example 267 and 1-bromo-2-ethoxyethane in place of1-bromo-2-methoxyethane, 20 mg (35%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.29 (s, 1H), 8.94 (d, J=2.7 Hz, 1H), 8.63(dd, J=2.4, 7.2 Hz, 1H), 7.87 (s, 1H), 7.58-7.46 (m, 3H), 7.40-7.36 (m,3H), 6.52 (s, 1H), 3.47 (t, J=6.3 Hz, 2H), 3.41 (q, J=6.9 Hz, 2H),3.06-2.95 (m, 3H), 2.48-2.46 (m, 2H), 2.13-2.06 (m, 2H), 1.97-1.93 (m,2H), 1.70-1.65 (m, 2H), 1.09 (t, J=6.9 Hz, 3H); MS [M+H]⁺=586.3; LCMSRT=2.54 min.

Example 245N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 241, using Example 242 in placeof Example 267 and 2-bromo-1,1-difluoroethane in place of1-bromo-2-methoxyethane, 23 mg (40%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.30 (s, 1H), 8.94 (d, J=2.1 Hz, 1H), 8.63(dd, J=2.4, 7.2 Hz, 1H), 7.87 (s, 1H), 7.58-7.46 (m, 3H), 7.413-7.35 (m,3H), 6.48 (s, 1H), 6.15 (tt, J=4.5, 55.8 Hz, 1H), 3.01-2.98 (m, 2H),2.79-2.70 (m, 2H), 2.30-2.26 (m, 2H), 2.19-2.13 (m, 2H), 1.73-1.69 (m,2H); MS [M+H]⁺=578.3; LCMS RT=2.50 min.

Example 246N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, using Example 242 in placeof Example 267, and glycolic acid in place of sodium2-hydroxypropanoate, 11 mg (20%) of the desired product was isolated.¹H-NMR (DMSO-d₆) δ 9.29 (s, 1H), 8.94 (d, J=3.0 Hz, 1H); 8.63 (dd,J=2.1, 7.5 Hz, 1H), 7.89 (s, 1H), 7.57-7.46 (m, 3H), 7.39-7.36 (m, 3H),6.52 (s, 1H), 4.50 (t, J=5.4 Hz, 1H), 4.12-4.09 (m, 2H), 3.79-3.75 (m,1H), 3.44-3.35 (m, 1H), 3.18-3.09 (m, 1H), 2.87-2.72 (m, 1H), 2.07-2.00(m, 2H), 1.67-1.50 (m, 2H); MS [M+H]⁺=572.5; LCMS RT=3.04 min.

Example 2474-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}-carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 232, using Example 242 in placeof Example 267, and dimethylcarbamic chloride in place ofmethanesulfonyl chloride 18 mg (26%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.29 (s, 1H), 8.94 (d, J=2.7 Hz, 1H), 8.63(dd, J=2.4, 6.9 Hz, 1H), 7.89 (s, 1H), 7.58-7.47 (m, 3H), 7.40-7.37 (m,3H), 6.54 (s, 1H), 3.67-3.62 (m, 2H), 2.87-2.80 (m, 3H), 2.73 (s, 6H),2.01-1.97 (m, 2H), 1.66-1.62 (m, 2H); MS [M+H]⁺=585.3; LCMS RT=3.15 min.

Example 248N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 235, using Example 242 in placeof Example 271, 19 mg (24%) of the desired product was isolated. ¹H-NMR(DMSO-d₆) δ 9.29 (s, 1H), 8.95 (s, 1H), 8.63 (dd, J=1.8, 7.2 Hz, 1H),7.88 (s, 1H), 7.58-7.43 (m, 3H), 7.39-7.36 (m, 3H), 6.50 (s, 1H),3.11-3.01 (m, 3H), 2.33-2.26 (m, 2H), 2.02-1.89 (m, 2H), 1.67-1.59 (m,3H), 1.17-1.07 (m, 1H), 0.43-0.29 (m, 3); MS [M+H]⁺=554.3; LCMS RT=2.42min.

Example 2491-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 108, using5-bromo-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine inplace of Intermediate V to provide 53 mg (17%) of the desired productwas isolated. ¹H-NMR (DMSO-d₆) δ 9.31 (s, 1H), 8.94 (s, 1H), 8.62 (dd,J=1.8, 7.5 Hz, 1H), 7.87 (s, 1H), 7.57-7.46 (m, 3H), 7.41-7.35 (m, 3H),6.56 (s, 1H), 3.58-3.54 (m, 4H), 3.04 (t, J=7.2 Hz, 2H), 2.63 (t, J=7.2Hz, 2H), 2.46-2.41 (m, 4H); MS [M+H]⁺=544.2; LCMS RT=2.82 min.

Example 2501-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 108, using5-bromo-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine inplace of Intermediate V and Intermediate AE in place of Intermediate M(N-[2-fluoro-5(trifluoromethyl)phenyl]-N′-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea),45 mg (13%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ10.13-10.0 (m, 2H), 8.54 (d, J=5.1 Hz, 1H), 8.26 (t, J=8.4 Hz, 1H), 8.01(s, 1H), 7.90 (s, 1H), 7.38-7.21 (m, 3H), 6.62 (s, 1H), 3.60-3.54 (m,4H), 3.04 (t, J=7.2 Hz, 2H), 2.63 (t, J=8.1 Hz, 2H), 2.45-2.39 (m, 4H);MS [M+H]⁺=545.1; LCMS RT=2.43 min.

Example 251N-{4-[4-amino-7-(1-hydroxyprop-2-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1: Preparation of1-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

In a manner similar to the procedure described for the preparation ofExample 268, using Intermediate O in place Intermediate AE, 727 mg (74%)of the desired product was isolated. MS [M+H]⁺=477.1; LCMS RT=3.47 min.

Step 2: Preparation of the Title Compound

To a stirred solution of1-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea(450 mg, 0.95 mmol) dissolved in THF (10 mL), was added vinyl magnesiumbromide (9.45 mL, 9.45 mmol, 1.0 M in THF) at rt. The reaction wasallowed to stir for 1 hr and then quenched with MeOH (1 mL). The mixturewas partitioned between EtOAc (250 mL) and saturated aq. Na₂CO₃ (100mL). The organic phase was washed with brine (100 mL), dried (Na₂SO₄),and concentrated to dryness. Trituration with Et₂O afforded 300 mg (63%)of the desired product. ¹H-NMR (DMSO-d₆) δ 8.65 (d, J=7.8 Hz, 1H), 8.27(t, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.36-7.27 (m, 5H), 7.13-7.07 (m, 1H),6.90 (s, 1H), 6.70-6.60 (m, 1H), 4.29 (dd, J=1.5, 5.7 Hz, 1H); MS[M+H]⁺=505.2; LCMS RT=2.85 min.

Example 252N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 101, using Example 253 in placeof Example 98, 5 mg (3%) of the desired product was isolated. ¹H-NMR(CD₃OD) δ 8.64 (d, J=8.1 Hz, 1H), 8.26 (t, J=8.7 Hz, 1H), 7.84 (s, 1H),7.36-7.25 (m, 4H), 6.71 (s, 1H), 5.40 (q, J=6.6 Hz, 1H), 1.61 (d, J=6.6Hz, 3H); MS [M+H]⁺=493.2; LCMS RT=2.84 min.

Example 253N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 103 Step 1, using IntermediateO in place of Intermediate M, 600 mg (78%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.43 (br s, 1H), 9.32 (br s, 1H), 8.66 (d,J=6.6 Hz, 1H), 8.30 (t, J=8.7 Hz, 1H), 8.14 (s, 1H), 7.57-7.46 (m, 1H),7.41-7.35 (m, 3H), 7.27 (d, J=8.4 Hz, 1H), 2.68 (s, 3H); MS[M+H]⁺=491.2; LCMS RT=3.46 min.

Example 254N-{4-[4-amino-7-(1,2-dihydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a stirred solution of Example 234 (150 mg, 0.30 mmol) in THF (2 mL)at 0° C., was added DIBAL-H (2.96 mL, 2.96 mmol, 1.0 M in THF). Thereaction was allowed to stir for 30 min while warming to rt. The mixturewas quenched with MeOH (1 mL) and diluted with EtOAc (300 mL) andsaturated aq sodium potassium tartrate (200 mL). This solution wasstirred at 50° C. for 17 hr. The mixture was allowed to cool and theorganic phase was washed with brine (50 mL), dried (Na₂SO₄) andconcentrated to dryness. The residue was purified by preparative HPLCusing a gradient elution from 10% to 70% acetonitrile to obtain 31 mg(20%) of the desired product. ¹H-NMR (DMSO-d₆) δ 9.51 (br s, 1H), 9.35(br s, 1H), 8.73 (d, J=6.0 Hz, 1H), 8.35 (t, J=8.7 Hz, 1H), 7.98 (s,1H), 7.62-7.55 (m, 1H), 7.49-7.47 (m, 1H), 7.41-7.27 (m, 2H), 6.76 (s,1H), 5.27 (t, J=5.7 Hz, 1H), 4.59-4.58 (m, 1H), 4.11 (s, 1H), 3.39 (d,J=6.9 Hz, 2H); MS [M+H]⁺=509.2; LCMS RT=2.98 min.

Example 255N-{4-[4-amino-7-(1,2,3-trihydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-flourophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 121, using Example 251 in placeof Example 117, 17 mg (16%) of the desired product was isolated. ¹H-NMR(CD₃OD) δ 8.64 (d, J=7.2, 1H), 8.25 (t, J=8.1 Hz, 1H), 7.83 (s, 1H),7.67-7.54 (m, 1H), 7.35-7.23 (m, 3H), 6.79 (s, 1H), 5.33 (d, J=6.6 Hz,1H), 4.14-4.11 (m, 1H), 3.74-3.63 (m, 2H); MS [M+H]⁺=539.3; LCMS RT=2.59min.

Example 2562-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-oxoethylacetate

To a stirred solution of Example 257 (350 mg, 0.62 mmol) in DMSO (3 mL),was added potassium acetate (302 mg, 3.07 mmol) at rt. The reaction wasallowed to stir for 15 min. The mixture was partitioned between EtOAc(100 mL) and saturated aq Na₂CO₃ (50 mL). The organic phase was dried(Na₂SO₄) and concentrated under reduced pressure. Trituration with Et₂Oafforded 150 mg (44%) of the desired product. ¹H-NMR (DMSO-d₆) δ 9.43(d, J=2.7 Hz, 1H), 9.30 (d, J=2.1 Hz, 1H), 8.65 (dd, J=2.1, 7.5 Hz, 1H),8.30 (t, J=8.7 Hz, 1H), 8.18 (s, 1H), 7.55-7.51 (m, 1H), 7.43-7.38 (m,2H), 7.37 (s, 1H), 7.27 (dd, J=1.8, 8.4 Hz, 1H), 5.44 (s, 2H), 2.14 (s,3H); MS [M+H]⁺=549.2; LCMS RT=3.60 min.

Example 257N-{4-[4-amino-7-(bromoacetyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 103 Step 2, using Example 253in place of Example 100, 340 mg (59%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 9.13 (d, J=3.0 Hz, 1H), 9.00 (d, J=2.4 Hz,1H), 8.35 (dd, J=2.1, 7.8 Hz, 1H), 8.01 (t, J=8.7 Hz, 1H), 7.89 (s, 1H),7.24-7.18 (m, 1H), 7.18 (s, 1H), 7.13-7.09 (m, 2H), 6.98 (dd, J=1.8, 8.4Hz, 1H), 4.63 (s, 2H); MS [M+H]⁺=569.4, 571.3; LCMS RT=3.81 min.

Example 258N-(4-{4-amino-7-[(3-morpholin-4-ylpropoxy)acetyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

To a stirred solution of Example 257 (200 mg, 0.351 mmol) in DMSO (1mL), was added diisopropylethylamine (435 μL, 2.64 mmol) and3-morpholin-4-ylpropan-1-ol (364 μL, 2.64 mmol) at rt. The reaction wasallowed to stir at 40° C. for 17 hr. The mixture was allowed to cool andpurified by preparative HPLC using a gradient elution from 10% to 70%acetonitrile to obtain 37 mg (17%) of the desired product. ¹H-NMR(DMSO-d₆) δ 9.62 (br s, 1H), 9.47 (br s, 1H), 8.65 (dd, J=2.4, 7.2 Hz,1H), 8.23 (t, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.54-7.47 (m, 1H), 7.42-7.38(m, 1H), 7.31 (dd, J=2.1, 12.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 6.88 (s,1H), 4.24 (d, J=11.7 Hz, 2H), 4.05-3.96 (m, 4H), 3.86-3.77 (m, 4H), 3.43(t, J=5.7 Hz, 2H), 3.24-3.20 (m, 2H), 1.91-1.85 (m, 2H); MS[M+H]⁺=634.2; LCMS RT=2.75 min.

Example 259N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 100 using Intermediate AE inplace of Intermediate M, 540 mg (58%) of the desired product wasisolated. ¹H-NMR (DMSO-d₆) δ 8.54 (d, J=5.1 Hz, 1H), 8.30 (t, J=8.1 Hz,1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.43-7.35 (m, 3H), 7.28 (dd, J=1.8, 8.4Hz, 1H), 2.68 (s, 3H); MS [M+H]⁺=474.0; LCMS RT=3.29 min.

Example 260N-(4-{4-amino-7-[(2-morpholin-4-ylethoxy)acetyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 258, using2-morpholin-4-ylethanol in place of 3-morpholin-4-ylpropan-1-ol, 20 mg(12%) of the desired product was isolated. ¹H-NMR (DMSO-d₆) δ 8.64 (d,J=7.2 Hz, 1H), 8.27 (t, J=8.1 Hz, 1H), 7.98 (s, 1H), 7.52-7.48 (m, 1H),7.41-7.38 (m, 1H), 7.33-7.19 (m, 2H), 6.82 (s, 1H), 4.52-4.47 (m, 2H),4.31-4.26 (m, 2H), 4.13-3.73 (m, 8H), 3.57-3.51 (m, 2H); MS[M+H]⁺=620.2; LCMS RT=2.74 min.

Example 2612-(4-{4-amino-5-[3-chloro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidin-1-yl)-N,N,N-trimethyl-2-oxoethanaminiumchloride

The title compound was prepared in a manner similar to the proceduredescribed for the preparation of Example 229, usingcarboxy-N,N,N-trimethylmethanaminium chloride in place of sodium2-hydroxypropanoate, 37 mg (59%) of the desired product was isolated.¹H-NMR (DMSO-d₆) δ 9.73 (d, J=2.7 Hz, 1H), 9.01 (s, 1H), 8.65 (dd,J=2.1, 7.5 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.92 (s, 1H), 7.52-7.49 (m,2H), 7.42-7.35 (m, 2H), 6.58 (s, 1H), 3.85-3.75 (m, 2H), 3.50-3.39 (m,2H), 3.24 (m, 9H), 2.85-2.55 (m, 1H), 2.15-2.02 (m, 2H), 1.96 (s, 2H),1.73-1.54 (m, 2H); MS [M]⁺=647.4; LCMS RT=2.60 min.

Example 262N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A solution of Example 275 (75 mg, 0.136 mmol),2-bromo-1,1-difluoroethane (40 mg, 0.27 mmol) and TEA (14 mg, 0.14 mmol)in 1 mL NMP were stirred at rt for 1 h and at 60° C. for 36 h. Thereaction was diluted with EtOAc and washed with aq. sodium carbonate.The volatiles were removed in vacuo to provide the title compound (52mg, 62%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.56 (s, 1H),9.55 (s, 1H), 8.71 (dd, 1H), 8.22 (dd, 1H), 7.97 (s, 1H), 7.55-7.66 (m,1H), 7.47-7.54 (m, 1H), 7.38 (dd, 1H), 6.62 (s, 1H), 6.23 (tt, J=56, 5Hz, 1H), 3.34-3.39 (m, 1H), 3.09-3.21 (m, 2H), 2.82 (td, J=16, 5 Hz,2H), 2.32-2.44 (m, 2H), 1.92-2.03 (m, 2H), 1.71-1.84 (m, 2H); ES-MS m/z614.3 [M+H]⁺, HPLC RT (min) 2.65.

Example 263N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A solution of Example 275 (122.8 mg, 0.223 mmol) in MeOH (2 mL) wastreated with acetic acid (134 mg, 2.24 mmol),[(1-methoxycyclopropyl)oxy](trimethyl)silane (234 mg, 1.34 mmol), sodiumcyanoborohydride (56 mg, 0.89 mmol) and 3A Molecular sieves was heatedat 60° C. overnight. The reaction was cooled to rt, diluted with EtOAcand washed with sodium carbonate solution. The organic layer was driedwith sodium sulfate and filtered thru a silica plug. The filtrate wasconcentrated and the residue purified by flash column (100% CH₂Cl₂ to 5%2N NH₃ in MeOH) to provide the title compound (23 mg, 21%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.55 (s, 1H), 9.51 (s, 1H), 8.71 (dd,1H), 8.22 (dd, 1H), 7.55 to 7.64 (m, 1H), 7.49 to 7.54 (m, 1H), 7.37(dd, 1H), 6.58 (s, 1H), 3.05 to 3.19 (m, 3H), 2.30 to 2.41 (m, 1H)2.0-2.08 (m, 2H), 1.60 to 1.76 (m, 4H), 0.46 to 0.52 (m, 2H), 0.33 to0.40 (m, 2H); ES-MS m/z 590.3 [M+H]⁺, HPLC RT (min) 2.53.

Example 264N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Prepared by the same method as Example 262 by substituting Example 267for Example 275. ¹H NMR (300 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.65 (dd,1H), 8.24 (d, 1H), 7.90 s, 1H), 7.36-7.58 (m, 5H), 6.60 (s, 1H), 6.15(tt, J=56, 4 Hz, 1H), 2.95-3.14 (m, 2H), 3.29-3.31 (m, 1H), 2.95-3.14(m, 2H), 2.75 (td, J=16, 4 Hz; 2H), 2.12-2.21 (m, 2H), 1.83-2.01 (m,2H), 1.62-1.79 (m, 2H). ES-MS m/z 612.3 [M+H]⁺, HPLC RT (min) 2.51.

Example 265N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Prepared by the same method as Example 263 by substituting Example 267for Example 275. ¹H NMR (300 MHz, DMSO-d₆) δ 9.51 (bs, 1H), 8.78 (bs,1H), 8.35 (dd, 1H), 7.93 (d, 1H), 7.13-7.30 (m, 2H), 7.05-7.10 (m, 2H),6.27 (s, 1H), 2.68-2.88 (m, 3H), 1.94-2.06 (m, 1H), 1.94-2.06 (m, 2H),1.61-1.68 (m, 1H), 1.28-1.41 (m, 3H), 0.08-0.17 (m, 2H), 0.03-0.04 (m,2H); ES-MS m/z 588.3 [M+H]⁺, HPLC RT (min) 2.48.

Example 266 tert-butyl4-(4-amino-5-{3-chloro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a flask charged with N₂ was added Intermediate AC (1.00 g, 3.79 mmol)and Intermediate AV (1.91 g, 4.16 mmol) followed by DMF (10 mL). N₂ wasbubbled through the solution for 15 min and then palladium acetate (85mg mg, 0.38 mmol) and triphenylphosphine (397 mg, 1.5 mmol) was addedfollowed by aq 2M Na₂CO₃ (2.5 mL, 5.0 mmol). N₂ was bubbled through thesolution for an additional 15 min and the reaction was then heated to80° C. for 17 h. The reaction material was allowed to cool to rt and wasdiluted with CH₂Cl₂. This suspension was filtered thru celite and thevolatiles removed in vacuo. The residue was taken up in CH₂Cl₂ andpurified with a short silica column (eluting with 1-5% MeOH in CH₂Cl₂).All fractions containing the product were combined and filtered thrusilica (removing most of the color) and the filtrate concentrated.Trituration in boiling ether gave the title compound (1.65 g, 67% yield)as a white solid. This material contained about 10% dehalogenatedstarting material. ¹H-NMR (DMSO-d₆) δ 9.73 (s, 1H), 9.00 (s, 1H), 8.65(dd, 1H), 8.24 (dd, J=8.5 Hz, 1H), 7.90 (s, 1H), 7.46-7.55 (m, 2H),7.40-7.45 (m, 1H), 7.38 (dd, 1H), 6.62 (s, 1H), 4.01-4.12 (m, 2H),3.28-3.35 (m, 1H), 2.75-2.98 (m, 2H), 1.91-2.02 (m, 2H), 1.55(ddd, 2H),1.42 (s, 9H); MS [M+H]⁺=648.2; LCMS RT=3.43 min.

Example 267N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-chlorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Example 266 (1.64 g, 2.53 mmol) in 50 mL1,2-dichloroethane was treated with 10 mL TFA at rt. The reactionquickly became homogeneous and at 10 min no starting material remainedby RP-HPLC. The reaction mixture was concentrated in vacuo, and theresidue taken up again in fresh 1,2-dichloroethane and concentratedagain; this was repeated 2 times. The residue was taken up in THF (15mL) and EtOAc (85 mL) and washed with aq. sodium carbonate. The organiclayer was dried with sodium sulfate and concentrated in vacuo to providea tan solid. Trituration with ethyl acetate provided the title compound(1.2 g, 87%) as a tan solid. ¹H-NMR (DMSO-d₆) δ 8.64 (dd, 1H), 8.23 (d,1H), 7.88 (s, 1H), 7.46-7.54 (m, 2H), 7.34-7.43 (m, 2H), 6.55 (s, 1H),3.17 (tt, 2H), 2.96-3.05 (m, 2H), 2.60 (dd, 2H), 1.60-1.85-1.95 (m, 2H),1.56 (ddd, 2H); MS [M+H]⁺=548.3; LCMS RT=2.94 min.

Example 268N-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

Step 1: Preparation of4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde

A solution of Intermediate B (4.25 g, 19.9 mmol) was suspended in 100 mLTHF and treated with 60% sodium hydride (798 rag, 19.9 mmol) and allowedto stir at rt for 30 min. The reaction mixture was then cooled to −78°C. and tert-butyllithium was added dropwise and the reaction allowed tostir for an additional 10 min. A solution of with DMF (15 mL) in THF (15mL) was added and the reaction stirred for an additional 10 min. Thereaction was then removed from the ice bath and allowed to warm up foran additional 30 min. The reaction was quenched with methanol (2 mL) anddiluted with ethyl acetate (200 mL) and pH 7 phosphate buffer (150 mL).The organic layer was washed with water (2 times), brine, dried withsodium sulfate and filtered thru a silica plug. Concentration of thefiltrate in vacuo provided a brown solid which H-NMR revealed to be a4:1 mixture of the desired product and Intermediate A. Suspension ofthis solid in a minimum of boiling MeOH and filtration of the solidprovided the title compound (1.78 g, 55%) as an off white solid. ¹H-NMR(DMSO-d₆) δ 10.25 (d, J=1 Hz, 1H), 8.21 (bs, 1H), 8.07 (s, 1H), 7.25 (d,J=5 Hz, 1H), 7.00 (dd, J=5, 1 Hz, 1H); MS [M+H]⁺=163.3; LCMS RT=1.14min.

Step 2: Preparation of the Title Compound

A solution of 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (1.781g, 10.98 mmol) in 25 mL DMF was cooled to −15° C. and treated with1,3-N,N-dibromo-4,4-dimethylhydantoin (3.30 g, 11.5 mmol). Reactionstirred for 30 min, the volatiles were removed in vacuo and the residuetriturated with hot methanol to provide the intermediate bromide as ayellow solid. This bromide was taken up in dioxane (70 mL,) and DMF (10mL) and Intermediate AE (3.43 g, 8.80 mmol) was added as a solid. Thesolution was degassed for 15 min with N₂ before the addition oftetrakis(triphenylphosphine)palladium(0) (851 mg, 0.74 mmol) and 2Msodium carbonate (7.34 mL, 14.7 mmol). The solution was again degassedwith N₂ for 15 min before heating to 80° C. overnight. After cooling tort, the reaction mixture was diluted with EtOAc (300 ml) and washed 2×with 1 N phosphate buffer (pH 7.0), 1× brine, dried over sodium sulfate,filtered and concentrated to dryness. Trituration of the residue withboiling ether provided the title compound (1.83 g, 36% 2 steps) as ayellow solid. ¹H-NMR (DMSO-d₆) δ 10.34 (s, 1H), 10.15 (bs, 1H), 10.10(bs, 1H), 8.56 (d, 1H), 8.31 (t, 1H), 8.16 (s, 1H), 8.01 (s, 1H),7.36-7.41 (m, 2H), 7.43 (d, 1H), 7.31 (s, 1H); MS [M+H]⁺=460.0; LCMSRT=3.39 min.

Example 269N-[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-(trifluoromethyl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea

Example 277 was prepared using the same procedure used for example 1, bysubstituting Intermediate AU for intermediate O. ¹H-NMR (DMSO-d₆) δ 9.74(s, 1H), 8.23 (s, 1H), 8.01-8.06 (m, 2H), 7.94 (s, 1H), 7.70-7.74 (m,1H), 7.70 (s, 1H), 7.50-7.58 (m, 1H), 7.56 (s, 1H), 7.41-7.46 (m, 1H),6.75 (s, 1H), 3.82 (s, 2H), 3.52-3.59 (m, 4H), 2.40-2.50 (m, 4H); MS[M+H]⁺=580.2; LCMS RT=2.66 min.

Example 270 tert-butyl4-(4-amino-5-{3-fluoro-4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a flask charged with N₂ was added Intermediate AC (850 mg, 2.15 mmol)and Intermediate AE (1.37 g, 3.22 mmol) followed by dioxane (20 mL). N₂was bubbled through the solution for 15 min and thentetrakis(triphenylphosphine)palladium (248 mg, 0.21 mmol) was addedfollowed by aq 2M Na₂CO₃ (3.2 mL, 6.4 mmol). N₂ was bubbled through thesolution for an additional 15 min and, then the reaction was heated to80° C. for 17 h. The reaction material was allowed to cool to rt and wasdiluted with CH₂Cl₂. This suspension was filtered thru celite and thevolatiles removed in vacuo. The residue was taken up in CH₂Cl₂ andpurified with a short silica column (eluting with 1-5% MeOH in CH₂Cl₂).All fractions containing the product were combined and filtered thrusilica (removing most of the color) and the filtrate concentrated.Trituration in boiling ether gave the title compound (934 mg, 71% yield)as a white solid. ¹H-NMR (DMSO-d₆) δ 8.53 (d, 1H), 8.26 (t, 1H), 8.01(s, 1H), 7.90 (s, 1H), 7.20-7.40 (m, 3H), 6.61 (s, 1H), 4.00-4.11 (m,2H), 3.25-3.39 (m, 1H), 2.77-3.00 (m, 2H), 1.91-2.02 (m, 2H), 1.54 (ddd,2H), 1.40 (s, 9H); MS [M+H]⁺=614.6; LCMS RT=3.29.

Example 271N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

A suspension of Example 270 (930 mg, 1.5 mmol) in 60 mL1,2-dichloroethane was treated with 15 mL TFA at rt. The reactionquickly became homogeneous and at 10 min no starting material remainedby RP-HPLC. The reaction mixture was concentrated in vacuo, and theresidue taken up again in fresh 1,2-dichloroethane and concentratedagain; this was repeated 2 times. The residue was taken up in THF (15mL) and EtOAc (85 mL) and washed with aq. sodium carbonate. The organiclayer was dried with sodium sulfate and concentrated in vacuo to providea tan solid. Trituration with ethyl acetate provided the title compound(705 mg, 91%) as a tan solid. ¹H-NMR (DMSO-d₆) δ 10.14 (bs, 1H), 10.06(bs, 1H), 8.54 (d, 1H), 8.26 (t, 1H), 8.01 (s, 1H), 7.88 (s, 1H),7.31-7.40 (m, 2H), 7.24 (dd, 1H), 6.65 (s, 1H), 3.18 (tt, 1H), 3.01(broad d, 2H), 2.61 (td, 2H), 1.92 (broad d, 2H), 1.54 (ddd, 2H); MS[M+H]⁺=515.2; LCMS RT=2.34.

Example 272 tert-butyl4-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

A solution of Intermediate AC (700 mg, 1.77 mmol) and Intermediate M(974 mg, 2.30 mmol) in 10 mL dioxane was treated with 5 mL DMF anddegassed well with N₂ gas. Tetrakis(triphenylphosphine)palladium (248mg, 0.21 mmol) was added followed by aq 2M Na₂CO₃ (3.2 mL, 6.4 mmol) andN₂ was bubbled through the solution for an additional 15 min. Thereaction was heated to 80° C. for 16 h. The reaction material wasallowed to cool to rt and was diluted with CH₂Cl₂. This suspension wasfiltered thru celite and the volatiles removed in vacuo. The residue wastaken up in CH₂Cl₂ and purified with a short silica column (eluting with1-5% MeOH in CH₂Cl₂). All fractions containing the product were combinedand filtered thru silica (removing most of the color) and the filtrateconcentrated. Trituration in boiling ether gave the title compound (437mg, 40% yield) as a white solid. ¹H-NMR (DMSO-d₆) δ 9.29 (s, 1H), 8.94(d, 1H), 8.62 (dd, 1H), 7.88 (s, 1H), 7.56 (d, 2H), 7.45-7.55 (m, 1H),7.38-7.43 (m, 2H), 1.55 (ddd, 2H), 1.40 (s, 9H); MS [M+H]⁺=614.0; LCMSRT=3.40 min.

Example 273N-{4-[4-amino-7-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

A solution of sodium methoxide in MeOH (25% by wt, 211 mg, 0.98 mmol)was taken up in MeOH (2 mL) and THF (8 mL) and the solution cooled to 0°C. Toluenesulfonylmethylisocyanide (96.6 mg, 0.49 mmol) andN-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea(150 mg, 0.33 mmol) were added in succession to the solution. Thereaction was stirred at 0° C. for 5 min, then heated at 60° C. for 1 h.The reaction was cooled to rt and diluted with EtOAc (100 mL). Theorganic layer was wash with water (2×) and dried with sodium sulfate.The suspension was filtered and the filtrate concentrated in vacuo. Theresulting solid was triturated with ether, and subsequently with THF toprovide the title compound (67 mg, 41%) as a tan solid. ¹H-NMR (DMSO-d₆)δ 9.43 (s, 1H), 9.30 (s, 1H), 8.65 (dd, 1H), 8.31 (t, 1H), 8.17 (s, 1H),7.52 (t, 1H), 7.37-7.46 (m, 2H), 7.26-7.32 (m, 1H), 7.23 (m, 1H); MS[M+H]⁺=499.1; LCMS RT=3.00 min.

Example 274 tert-butyl4-(4-amino-5-{2,5-difluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate

To a flask charged with N₂ was added Intermediate AC (1.00 g, 2.52 mmol)and Intermediate AH (1.28 g, 2.78 mmol) followed by DMF. (10 mL). N₂ wasbubbled through the solution for 15 min and thentetrakis(triphenylphosphine)palladium (292 mg, 0.252 mmol) was addedfollowed by aq 2M Na₂CO₃ (2.5 mL, 5.0 mmol). N₂ was bubbled through thesolution for an additional 15 min and, then the reaction was heated to80° C. for 17 h. The reaction material was allowed to cool to rt and wasdiluted with CH₂Cl₂. This suspension was filtered thru celite and thevolatiles removed in vacuo. The residue was taken up in CH₂Cl₂ andpurified with a short silica column (eluting with 1-5% MeOH in CH₂Cl₂).All fractions containing the product were combined and filtered thrusilica (removing most of the color) and the filtrate concentrated.Trituration in boiling ether gave the title compound (980 mg, 59% yield)as a white solid. ¹H-NMR (DMSO-d₆) δ 9.48 (s, 1H), 9.43 (s, 1H), 8.63(dd, 1H), 8.14 (dd, 1H), 7.90 (s, 1H), 7.39-7.54 (m, 3H), 7.30 (dd, 1H),6.55 (s, 1H), 4.05 (bd, 2H), 3.56-3.63 (m, 1H), 2.86 (br s, 2H),1.89-2.02 (m, 2H), 1.53 (ddd, 2H), 1.40 (s, 9H); MS [M+H]⁺=650.2; LCMSRT=3.45 min.

Example 275N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,5-difluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of Example 274 (498 mg, 0.77 mmol) in 10 mL1,2-dichloroethane was treated with 3 mL TFA at rt. The reaction quicklybecame homogeneous and at 10 min no starting material remained byRP-HPLC. The reaction mixture was concentrated in vacuo, and the residuetaken up again in fresh 1,2-dichloroethane and concentrated again; thiswas repeated 2 times. The residue was taken up in THF (5 mL) and EtOAc(35 mL) and washed with aq. sodium carbonate. The organic layer wasdried with sodium sulfate and concentrated in vacuo to provide a tansolid. Trituration with ethyl acetate provided the title compound (178mg, 42%) as a tan solid. Concentration of the mother liquor provided anadditional the title compound (201 mg, 48 mmol) of similar purity.¹H-NMR (DMSO-d₆) δ 9.54 (bs, 2H), 8.70 (dd, 1H), 8.21 (dd, 1H), 7.96 (s,1H), 7.60 (dd, 1H), 7.30-7.46 (m, 1H), 7.38 (dd, 1H), 6.57 (s, 1H),3.16-3.31 (m, 1H), 3.02-3.12 (m, 2H), 2.60-2.74 (m, 2H), 1.89-2.02 (m,2H), 1.60 (ddd, 2H), 1.42 (s, 9H); MS [M+H]⁺=550.2; LCMS RT=2.43

Example 276N-{4-[4-amino-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

A suspension of the product formed in step 4 of Example 289 (100 mg,0.15 mmol) in triethylsilane (1 mL) was treated with borontrifluoridediethyl etherate (50 μL, 0.39 mmol) and heated to 80° C. in a sealedtube for 1 h. The reaction was quenced with 2N NaOH (2 mL) and dilutedwith ether. The ether layer was separated. The aqueous was thenextracted with EtOAc. The EtOAc layer was dried (MgSO₄) andconcentrated. The crude residue was purified over silica (MPLC, 10-25%MeOH/CH₂Cl₂). A pale yellow solid was isolated (25 mg, 30%). ¹H-NMR(CD₃OD) δ 8.64 (d, J=7.7 Hz, 1H), 8.26 (t, J=8.6 Hz, 1H), 7.84 (s, 1H),7.36-7.26 (m, 4H), 6.64 (s, 1H), 4.10-3.98 (m, 2H), 3.73 (dd, J₁=12 Hz,J₂=3.3 Hz, 1H), 3.22-2.97 (m, 5H), 2.83 (dd, J₁=13 Hz, J₂=11 Hz, 1H); MS[M+H]⁺=548.2; LCMS RT=2.87 min.

Example 277N-[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-(trifluoromethoxy)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Example 277 was prepared using the same procedure used for Example 1, bysubstituting Intermediate AL for Intermediate O. ¹H-NMR (DMSO-d₆) δ 9.61(s, 1H), 9.12 (s, 1H), 8.61-8.67 (m, 1H), 8.36 (d, 1H, 7.92 (s, 1H),7.37-7.56 (m, 5H), 6.70 (s, 1H), 3.82 (s, 2H), 3.50-3.85 (m, 4H),2.40-2.48 (m, 4H); MS [M+H]⁺=614.0; LCMS RT=3.03 min.

Example 278N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-(4-tert-butylpyridin-2-yl)urea

Step 1. Preparation of5-(4-amino-3-methylphenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

The procedure used for the preparation of Intermediate E was used toprepare the title compound by substituting Intermediate AK for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in step 4. ¹H-NMR(DMSO-d₆) δ 7.84 (s, 1H), 7.03-6.96 (m, 2H), 6.68 (d, J=8.0 Hz, 1H),6.50 (s, 1H), 5.03 (s, 2H), 3.79 (s, 2H), 3.56-3.53 (m, 4H), 2.46-2.40(m, 4H), 2.09 (s, 3H); MS [M+H]⁺=339.0; LCMS RT=1.02 mm.

Step 2. Preparation of the Title Compound

The procedure used for the preparation of Example 2 was used to preparethe title compound by substitutingphenyl(4-tert-butylpyridin-2-yl)carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate and5-(4-amino-3-methylphenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminefor Intermediate E. ¹H-NMR (DMSO-d₆) δ 9.76 (s, 1H), 8.22-8.19 (m, 2H),7.90 (s 1H), 7.34-7.25 (m, 3H), 7.08 (dd, J₁=5.6 Hz, J₂=1.7 Hz, 1H),6.62 (s, 1H), 3.83 (s, 2H), 3.56 (t, J=4.1 Hz, 4H), 2.49-2.44 (m, 4H),2.39 (s, 3H), 1.26 (s, 9H); MS [M+H]⁺=515.1; LCMS RT=2.21 min.

Example 279N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-(2-fluoro-5-methylphenyl)urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting 1-fluoro-2-isocyanato-4-methylbenzenefor 2-fluoro-5-(trifluoromethyl)phenyl isocyanate and Example 278, step1 for Intermediate E. ¹H-NMR (DMSO-d₆) δ 9.02 (s, 1H), 8.47 (s, 1H),8.05-8.00 (m, 2H), 7.90 (s 1H), 7.30-7.23 (m, 2H), 7.11 (dd, J₁=11.5 Hz,J₂=7.9 Hz, 1H), 6.82-6.77 (m, 1H), 6.62 (s, 1H), 3.82 (s, 2H), 3.56 (t,J=4.7 Hz, 4H), 2.47-2.41 (m, 4H), 2.31 (s, 3H), 2.67(s, 3H); MS[M+H]⁺=490.3; LCMS RT=1.82 min.

Example 280N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting1-chloro-2-isocyanato-4-(trifluoromethyl)benzene for2-fluoro-5-(trifluoromethyl)phenyl isocyanate and Example 278, step 1for Intermediate E. ¹H-NMR (DMSO-d₆) δ 8.63 (d, J=2.4 Hz, 1H), 7.93 (s,1H), 7.91 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.38 (dd, J₁=8.4 Hz, J₂=1.6Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 7.26 (dd, J₁=8.4 Hz, J=2.7 Hz, 1H),6.63 (s, 1H), 3.83 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.48-2.42 (m, 4H),2.33 (s, 3H); MS [M+H]⁺=560.2, 562.2; LCMS RT=2.49 min.

Example 281N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 4 was used to preparethe title compound by substituting1-isocyanato-3-(trifluoromethyl)benzene for2-fluoro-5-(trifluoromethyl)phenyl isocyanate and5-(4-amino-3-methylphenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(Example 278, step 1) for Intermediate E. ¹H-NMR (DMSO-d₆) δ 8.06 (s.1H), 7.93 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.59-7.49 (m, 2H), 7.32-7.29(m, 2H), 7.25 (dd, J₁=8.3.Hz, J₂=2.3 Hz, 1H), 6.62 (s, 1H), 3.82 (s,2H), 3.56 (t, J=4.5 Hz, 4H), 2.48-2.41 (m, 4H), 2.31 (s, 3H); MS[M+H]⁺=526.2; LCMS RT=2.40 min.

Example 282 tert-butyl2-({[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate

Step 1: Preparation of 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylicacid

A suspension of Intermediate B (2.0 g, 9.93 mmol) in THF (100 mL) wascooled to −78° C. and slowly treated with a 1.7 N solution of nBuLi inhexanes (27.6 mL, 46.9 mmol). The suspension was stirred for 1 hr beforebubbling in dry CO₂. The gas was bubbled in for 1 hr before the reactionwas quenched with water and allowed to warm to rt. A precipitate formedin the aqueous layer. The biphasic mixture was filtered. The motherliquor was concentrated and diluted with water. The remaining solid wasfiltered and rinsed with water. This process was repeated three times toyield an off-white solid (1.4 g, 85%). MS [M+H]⁺=179.2; LCMS RT=1.12min.

Step 2: Preparation of tert-Butyl2-({[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate

4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid (215 mg, 1.21mmol) was combined with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (347 mg, 1.81 mmol) and 1-hydroxybenzotriazole monohydrate(245 mg, 1.81 mmol) in DMF (5 mL). The mixture was stirred at rt for 30min. before adding tert-butyl 2-(aminomethyl)morpholine-4-carboxylate(274 mg, 1.27 mmol). After 1 hr, the reaction was poured into satd.NaHCO₃ solution and stirred for 1 h. The product was collected by vacuumfiltration to give a tan solid (400 mg, 88%). MS [M+H]⁺=377.0; LCMSRT=2.71 min.

Step 3: Preparation of tert-butyl2-({[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate

A solution of tert-butyl2-({[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate(100 mg, 0.27 mmol) in THF (5 mL) was cooled to −50° C. and treated with1,3-dibromo-5,5-dimethylhydantoin (37 mg, 0.13 mmol) in portions over 30min. The reaction was then quenched with satd. Na₂SO₃ and warmed to rt.The product was extracted with EtOAc, dried (MgSO₄), and concentrated.The crude product was triturated with EtOAc and filtered. A white solidwas collected (60 mg, 50%). MS [M+H]⁺=545.96, 456.86; LCMS RT=2.90 min.

Step 4: Preparation of the Title Compound

tert-Butyl-2-({[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate(60 mg, 0.13 mmol) was dissolved in DMF (0.5 ml) and added to a solutionof Intermediate O (62 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL). Themixture was degassed three times then treated with Na₂CO₃ (2N, 127 μL,0.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.004mmol). The mixture was degassed again and heated to 80° C. for 2 h. Thereaction was cooled and pulled through a plug of silica andconcentrated. The crude residue was triturated with 10% EtOAc/Hex andthe desired product was collected by vacuum filtration to yield a tansolid (60 mg, 60%). ¹H-NMR (DMSO-d₆) δ 9.44 (bs, 1H), 9.29 (bs, 1H),9.19 (t, J=5.8 Hz, 1H), 8.66 (d, J=4.4 Hz, 1H), 8.30 (t, J=8.7 Hz, 1H),8.17 (s, 1H), 7.52 (t, J=9.8 Hz, 1H), 7.44-7.38 (m, 2H), 7.27 (d, J=8.2Hz, 1H), 7.24 (s, 1H), 3.89-3.82 (m, 2H), 3.73-3.36 (m, 4H), 2.88-2.55(m, 2H), 2.47-2.43 (m, 1H), 1.39 (s, 9H); MS [M+H]⁺=691.0; LCMS RT=3.66min.

Example 2834-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

tert-Butyl-2-({[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]aminocarbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-carbonyl]amino}methyl)morpholine-4-carboxylate(55 mg, 0.08 mmol) was suspended in 1,4-dioxane (1 mL) and treated with4N HCl in dioxane (100 μL) and stirred at rt for 1 h. The suspension wasconcentrated then diluted with satd. NaHCO₃ and extracted with EtOAc.The organic layer was dried (MgSO₄) and concentrated. The crude samplewas then triturated with EtOAc. The desired product was collected byvacuum filtration (47 mg, 99%). ¹H-NMR (DMSO-d₆) δ 9.44 (bs, 1H), 9.30(bs, 1H), 9.16 (m, 1H), 8.67 (d, J=7.0 Hz, 1H), 8.30 (t, J=8.3 Hz, 1H),8.16 (s, 1H), 7.53 (t, J=9.6 Hz, 1H), 7.44-7.38 (m, 2H), 7.27 (d, J=8.0Hz, 1H), 7.23 (s, 1H), 3.77 (d, J=10.7 Hz, 1H), 3.55-3.40 (m, 4H), 2.82(d, J=12 Hz, 1H), 2.71-255 (m, 3H), 2.47-2.38 (m, 1H); MS [M+H]⁺=591.2;LCMS RT=2.58 min.

Example 284N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 282 was used toprepare the title compound by substituting(2R)-2-(methoxymethyl)pyrrolidine for tert-butyl2-(aminomethyl)morpholine-4-carboxylate in step 2. ¹H-NMR (CD₃OD) δ 8.65(d, J=8.4 Hz, 1H), 8.30 (t, J=8.4 Hz, 1H), 7.92 (s, 1H), 7.37-7.29 (m,4H), 6.93 (s, 1H), 4.73-4.55 (m, 2H), 4.47-4.39(m, 1H), 3.69-3.54 (m,2H), 3.42 (s, 3H), 3.15-3.03 (m, 1H), 2.17-1.91 (m, 3H); MS[M+H]⁺=590.8; LCMS RT=3.33 min.

Example 285N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 282 was used toprepare the title compound by substituting(2R)-2-(methoxymethyl)pyrrolidine for tert-butyl2-(aminomethyl)morpholine-4-carboxylate in step 2 and Intermediate AFfor Intermediate O in step 4. ¹H-NMR (CD₃OD) δ 8.64 (d, J=8.1 Hz, 1H),7.91 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.39-7.32 (m, 4H), 6.90 (s, 1H),4.674.60 (m, 2H), 4.47-4.39(m, 1H), 3.69-3.55 (m, 2H), 3.42 (s, 3H),3.11-3.03 (m, 1H), 2.39,(s, 3H), 2.19-1.93 (m, 3H); MS [M+H]⁺=586.7;LCMS RT=3.26 min.

Example 286N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 282 was used toprepare the title compound by substituting(2R)-2-(methoxymethyl)pyrrolidine for tert-butyl2-(aminomethyl)morpholine-4-carboxylate in step 2 and Intermediate Q forIntermediate O in step 4. ¹H-NMR (CD₃OD) δ 8.24 (t, J=8.5 Hz, 1H), 7.96(s, 1H), 7.92 (s, 1H), 7.62 (d, J=9.2 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H),7.36-7.28 (m, 3H), 6.93 (s, 1H), 4.66-4.60 (m, 2H), 4.46-4.40(m, 1H),3.68-3.53 (m, 2H), 3.42 (s, 3H), 3.12-3.04 (m, 1H), 2.18-1.96 (m, 3H);MS [M+H]⁺=572.3; LCMS RT=3.05 min.

Example 287N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea

Step 1. Preparation ofphenyl[1-oxido-4-(trifluoromethyl)pyridin-2-yl]carbamate

Intermediate H was (300 mg, 1.06 mmol) was suspended in CHCl₃ (5 mL) andtreated with m-CPBA (238 mg, 1.06 mmol). The reaction was stirred at rtovernight. The reaction was quenched with satd. NaHCO₃ and extractedwith CHCl₃. The organic layer was dried (MgSO₄) and concentrated. Thecrude residue was purified over silica using CH₂Cl₂ as the elutingsolvent (260 mg, 82%); ¹H-NMR (DMSO-d₆) δ 8.53-8.49 (mn, 2H), 7.49-7.41(m, 3H), 7.33-7.25 (m, 3H); MS [M+H]⁺=299.1; LCMS RT=2.99 min.

Step 2. Preparation of the Title Compound

The procedure used for the preparation of Example 2 was used to preparethe title compound by substitutingphenyl[1-oxido-4-(trifluoromethyl)pyridin-2-yl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate and5-(4-amino-3-fluorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminefor Intermediate E. ¹H-NMR (DMSO-d₆) δ 10.82 (s, 1H), 10.01 (s, 1H),8.61 (d, J=2.1 Hz, 1H), 8.57 (d, J=7.0, 1H), 8.22 (t, J=8.5, 1H), 7.92(s, 1H), 7.44 (dd, J₁=7.0 Hz, J₂=2.8 Hz, 1H), 7.36 (dd, J₁=12 Hz, J₂=2.0Hz, 1H), 7.27(dd, J₁=8.3 Hz, J₂=1.7 Hz, 1H), 6.69 (s, 1H), 3.82 (s, 2H),3.55 (t, J=4.4, 4H), 2.47-2.41 (m, 4H); MS [M+H]⁺=547.1; LCMS RT=2.14min.

Example 288N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 287 was used toprepare the title compound by substituting Intermediate E for5-(4-amino-3-fluorophenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminein step 2. ¹H-NMR (DMSO-d₆) δ 10.34 (s, 1H), 10.19 (s, 1H), 8.60 (d,J=2.8 Hz, 1H), 8.58 (d, J=6.8, 1H), 7.91 (s, 1H), 7.60 (d, J=8.6 Hz,2H), 7.43 (d, J=8.4 Hz, 3H), 6.64 (s, 1H), 3.82 (s, 2H), 3.56 (t, J=4.6,4H), 2.47-2.41 (m, 4H); MS [M+H]⁺=529.3; LCMS RT=2.14 min.

Example 289N-{4-[4-amino-7-(morpholin-2-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

Step 1. Preparation of tert-butyl2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate

Commercially available 4-(tert-butoxycarbonyl)morpholine-2-carboxylicacid (1.95 g, 8.43 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimidehydrochloride (1.94 g, 10.1 mmol) and 1-hydroxybenztriazole monohydrate(1.25 g, 9.28 mmol) were combined in DMF (10 mL) and stirred at rt for15 min. before adding N,O-dimethylhydroxylamine (0.987 g, 10.1 mmol),The reaction was stirred at rt overnight. The reaction was thenconcentrated and partitioned between saturated NaHCO₃ and 20%isopropanol in CHCl₃. The organic layer was dried (MgSO₄) andconcentrated. The crude residue was pulled through a layer of silicausing CH₂Cl₂ and the eluting solvent. A colorless oil was isolated (0.7g, 30%). ¹H-NMR (DMSO-d₆) δ 4.31-4.18 (bs, 1H), 3.94-3.78 (m, 2H),3.76-3.61 (m, 4H), 3.48 (dt, J₁=11 Hz, J₂=2.7 Hz, 1H), 3.19-2.80 (m,5H), 1.39 (s, 9H).

Step 2. Preparation of tert-butyl2-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]morpholine-4-carboxylate

A suspension of Intermediate B (0.45 g, 2.11 mmol) in THF (5 mL) wastreated with chlorotrimethylsilane (0.54 mL, 4.23 mmol) and stirred atrt overnight. The suspension was then cooled to 0° C. and slowly treatedwith isopropylmagnesium chloride (4.2 mL, 8.45 mmol). The suspensionquickly went into solution and was stirred at rt for 2 h, checking byTLC for the disappearance of Intermediate B. The amber solution wasagain cooled to 0° C. then slowly treated with a solution of tert-butyl2-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate (0.7 g, 2.54 mmol)in THF (1 mL). The reaction was then stirred at rt overnight. Thereaction was then poured into satd. NH₄Cl solution and stirred for 15min. The product was extracted with EtOAc, dried (MgSO₄) andconcentrated. The residue was triturated with EtOAc and filtered. A paleyellow solid was collected (0.65 g, 88%). ¹H-NMR (DMSO-d₆) δ 8.25-8.10(m, 2H), 8.07 (s, 1H), 7.39 (d, J=5.0 Hz, 1H), 7.1 (d, J=4.7 Hz, 1H),5.13-5.00 (m, 1H), 4.00-3.90 (m, 2H), 3.69-3.55 (m, 2H), 3.10-3.00 (m,2H), 1.35 (bs, 9H); MS [M+H]⁺=348.2; LCMS RT=2.66 min.

Step 3. Preparation of tert-butyl2-[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]morpholine-4-carboxylate

A solution of tert-butyl2-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]morpholine-4-carboxylate(0.66 g, 1.90 mmol) in THF (5 mL) was cooled to −50° C. and stirred for1 h before adding 1.3-dibromo-5,5-dimethylhydantoin (0.27 g, 0.94 mmol)in portions. The reaction was then quenched with satd. Na₂SO₃ solution.The product was extracted with EtOAc, dried (MgSO₄) and concentrated.The crude solid was triturated with EtOAc and filtered. An off-whitesolid was isolated (530 mg, 65%). ¹H-NMR (DMSO-d₆) δ 8.10 (s, 1H), 7.54(s, 1H), 5.05-4.95 (m, 1H), 4.00-3.89 (m, 2H), 3.69-3.55 (m, 2H),3.10-3.00 (m, 2H), 1.33 (bs, 9H).

Step 4. Preparation of tert-butyl2-({4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}carbonyl)morpholine-4-carboxylate

The procedure used for the preparation of Example 7 was used to preparethe title compound by substituting tert-butyl2-[(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]morpholine-4-carboxylatefor Intermediate C and Intermediate O for Intermediate R. MS [M+H]⁺=662.1; LCMS RT 3.50 min.

Step 5. Preparation of the Title Compound

A solution of tert-butyl2-({4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}carbonyl)morpholine-4-carboxylate(50 mg, 0.076 mmol) in 1,4-dioxane (1 mL) was treated with 4N HCl (200μL) in 1,4-dioxane and stirred at rt for 4 h. The reaction wasconcentrated then diluted with EtOAc and saturated NaHCO₃ solution. Theorganic layer was dried (MgSO₄) and concentrated. The crude residue wastriturated with EtOAc and filtered. A yellow solid was isolated (24 mg,57%). ¹H-NMR (CD₃OD) δ 8.65 (d, J=8.2 Hz, 1H), 8.32 (t, J=8.5 Hz, 1H),8.09 (s, 1H), 7.48 (s, 1H), 7.34-7.29 (m, 4H), 5.26 (dd, J₁=9.6 Hz,J₂=2.6 Hz, 1H), 4.65-4.60 (m, 1H), 4.00 (dt, J₁=11.6 Hz, J₂=2.5 Hz, 1H),3.82-3.75 (m, 1H), 2.89-2.86 (m, 2H), 2.75 (dd, J₁=12.8 Hz, J₂=9.6 Hz,1H); MS [M+H]⁺=562.1; LCMS RT=2.66 min.

Example 290N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 282 was used toprepare the title compound by substituting 1-methylpiperazine fortert-butyl 2-(aminomethyl)morpholine-4-carboxylate in step 2 andIntermediate M for Intermediate O in step 4. ¹H-NMR (CD₃OD) δ 8.62 (d,J=7.6 Hz, 1H), 7.91 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.7 Hz,2H), 7.34 (d, J=8.8 Hz, 2H), 6.88 (s, 1H), 3.90-3.78 (m, 2H), 3.50-3.40(m, 2H), 2.62-2.44 (m, 4H), 2.35 (s, 3H); MS [M+H]⁺=557.2; LCMS RT=2.56min.

Example 291N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 282 was used toprepare the title compound by substituting 1-methylpiperazine fortert-butyl 2-(aminomethyl)morpholine-4-carboxylate in step 2 andIntermediate Q for Intermediate O in step 4. ¹H-NMR (CD₃OD) δ 8.23 (t,J=8.4 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.49(t, J=7.9 Hz, 1H), 7.36-7.28 (m, 3H), 6.90 (s, 1H), 3.90-3.79 (m, 2H),3.50-3.439 (m, 2H), 2.62-2.44 (m, 4H), 2.35 (s, 3H); MS [M+H]⁺=557.2;LCMS RT=2.59 min.

Example 2924-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]-amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

The procedure used for the preparation of Example 282 and 283 was usedto prepare the title compound by substituting Intermediate M forIntermediate O in step 4 of Example 282. ¹H-NMR (DMSO-d₆) δ 9.34 (s,1H), 9.14 (t, J=5.4 Hz, 1H), 8.97 (s, 1H), 8.63 (d, J=7.1, 1H), 8.15 (s,1H), 7.60 (d, J=8.6 Hz, 2H), 7.51 (t, J=10.0 Hz, 1H), 7.44-7.38 (m, 3H),7.18 (s, 1H), 3.76 (d, J=11 Hz, 1H), 3.55-3.38 (m, 4H), 2.80 (d, J=12.3Hz, 1H), 2.69-2.57 (m, 2H), 2.45-2.37 (m, 1H); MS [M+H]⁺=573.2; LCMSRT=2.54 min.

Example 2934-amino-5-{3-fluoro-4-[({[3-(trifluoromethyl)phenyl]-amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazine-7-carboxamide

The procedure used for the preparation of Example 282 and 283 was usedto prepare the title compound by substituting Intermediate Q forIntermediate O in step 4 of Example 282. ¹H-NMR (DMSO-d₆) δ 9.49 (s,1H), 9.15 (t, J=5.3 Hz, 1H), 8.80 (s, 1H), 8.25 (t, J=8.4, 1H), 8.16 (s,1H), 8.05 (bs, 1H), 7.55-7.53 (m, 2H), 7.39 (dd, J₁=12.1 Hz, J₂=2.1 Hz,1H), 7.35-7.33 (m, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.22 (s, 1H), 3.76 (d,J=8.8 Hz, 1H), 3.52-341 (m, 4H), 2.80 (d, J=11.2 Hz, 1H), 2.69-2.57 (m,2H), 2.45-2.37 (m, 1H); MS [M+H]⁺=573.2; LCMS RT=2.56 min.

Example 2944-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}-carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

The procedure used for the preparation of Example 282 and 283 was usedto prepare the title compound by substituting Intermediate N forIntermediate O in step 4 of Example 282. ¹H-NMR (DMSO-d) δ 10.2-10.13(bs, 1H), 9.16-9.13 (m, 2H), 8.58 (s, 1H), 8.15 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.6 Hz, 2H), 7.38 (d, J=9.1Hz, 1H), 7.18 (s, 1H), 3.76 (d, J=11 Hz, 1H), 3.55-3.38 (m, 4H), 2.79(d, J=12 Hz, 1H), 2.67-2.59 (m, 2H), 2.46-2.38 (m, 1H); MS [M+H]⁺=589.2,591.1; LCMS RT=2.61 min.

Example 2954-amino-5-{2,5-difluoro-4-[({[2-fluoro-5-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide

The procedure used for the preparation of Example 282 and 283 was usedto prepare the title compound by substituting Intermediate AH forIntermediate O in step 4 of Example 282. ¹H-NMR (DMSO-d₆) δ 9.49 (d,J=12 Hz, 2H), 9.14 (t, J=5.7 Hz, 1H), 8.63 (dd, J₁=7.2, J₂=2.0, 1H),8.20-8.15 (m, 2H), 7.56-7.53 (m, 1H), 7.46-7.37 (m, 2H), 7.20 (s, 1H),3.74 (d, J=11 Hz, 1H), 3.55-3.38 (m, 4H), 2.79 (d, J=11.3 Hz, 1H),2.70-2.59 (m, 2H), 2.43-2.38 (m, 1H); MS [M+H]⁺=609.2; LCMS RT=2.65 min.

Example 2961-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea

Step 1. Preparation of4-chlorophenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate

The procedure used for the preparation of Example 299 was used toprepare the title compound by substituting 4-chlorophenyl chloroformatefor isopropenyl chloroformate in step 1. ¹H-NMR (DMSO-d₆) δ 9.66 (s,1H), 9.22 (d, J=7.1 Hz, 1H), 8.03 (s, 1H), 7.47 (dd, J₁=7.0 Hz, J₂=2.1Hz, 1H), 7.18 (d, J=8.9 Hz, 2H), 6.75 (d, J=8.6 Hz, 2H); MS[M+H]⁺=333.1, 335.1; LCMS RT=3.38 min.

Step 2. Preparation of the Title Compound

4-chlorophenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (35 mg, 0.098mmol) and5-(4-amino-3-fluorophenyl)-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine(36 mg, 0.11 mmol) were combined in 1,4-dioxane (1 mL) and treated withN,N-diisopropylamine (34 mL, 0.20 mmol). The reaction was heated to 80°C. overnight. The reaction was then concentrated and purified oversilica (0-20%, MeOH/CH₂Cl₂) to yield an orange solid (13 mg, 24%).¹H-NMR (DMSO-d₆) δ 10.83 (d, J=5.1 Hz, 1H), 10.09 (s, 1H), 8.61 (d,J=2.4 Hz, 1H), 8.57 (d, J=6.6 Hz, 1H), 8.22 (td, J₁=9.2 Hz, J₂=2.4 Hz,1H), 7.92 (s, 1H), 7.44 (dd, J₁=6.7 Hz, J₂=2.9 Hz, 1H), 7.36 (dd,J₁=12.1 Hz, J₂=2.0 Hz, 1H), 7.27 (dd, J₁=8.3 Hz, J₂=1.6 Hz, 1H), 6.69(s, 1H), 3.99 (s, 2H), 3.67 (t, J=6.0 Hz, 2H), 3.61-3.59 (m, 2H),2.75-2.68 (m, 4H), 1.80 (q, J=5.7 Hz, 2H); MS [M+H]⁺=561.0; LCMS RT=1.62min.

Example 297N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 282 was used toprepare the tide compound by substituting 1-methylpiperazine fortert-butyl 2-(aminomethyl)morpholine-4-carboxylate in step 2 andIntermediate AE for Intermediate O in step 3. ¹H-NMR (CD₃OD) δ 8.51 (d,J=5.3 Hz, 1H), 8.34 (t, J=8.3 Hz, 1H), 7.93 (s, 1H), 7.67 (s, 1H), 7.38(dd, J₁=11.7 Hz, J₂=1.9 Hz, 1H), 7.33-7.29 (m, 2H), 6.92 (s, 1H),3.90-3.79 (m, 2H), 3.50-3.439 (m, 2H), 2.62-2.44 (m, 4H), 2.35 (s, 3H);MS [M+H]⁺=558.1; LCMS RT=2.34 min.

Example 2981-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea

The procedure used for the preparation of Example 296 was used toprepare the title compound by substituting5-(4-aminophenyl)-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminefor5-(4-amino-3-fluorophenyl)-7-(1,4-oxazepan-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-aminein step 2. ¹H-NMR (DMSO-d₆) δ 10.35 (d, J=2.0 Hz, 1H), 10.20 (d, J=3.3Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.58 (d, J=6.7 Hz, 1H), 7.90 (s, 1H),7.60 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.5 Hz, 3H), 6.65 (s, 1H), 4.00 (s,2H), 3.66 (t, J=6.1 Hz, 2H), 3.61-3.59 (m, 2H), 2.75-2.68 (m, 4H), 1.81(q, J=5.7 Hz, 2H); MS [M+H]⁺=543.0; LCMS RT=1.86 min.

Example 299N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea

Step 1. Preparation of isopropenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate

4-(trifluoromethyl)pyridin-2-amine (1.0 g, 6.17 mmol) was dissolved inTHF (20 mL) and treated with pyridine (600 μL, 7.4 mmol) and isopropenylchloroformate (596 μL, 6.17 mmol). The reaction was stirred at rt for 6h. The reaction was then concentrated and triturated with EtOAc. Thecrude residue was purified by MPLC (100% CH₂Cl₂) to yield a pale yellowsolid (1.2 g, 79%); ¹H-NMR (DMSO-d₆) δ 11.0 (s, 1H), 8.57 (d, J=5.1 Hz,1H), 8.10 (s, 1H), 7.45 (d, J=5.5 Hz, 1H), 4.81 (t, J=1.1 Hz, 1H), 4.76(s, 1H), 1.94 (s, 3H).

Step 2. Preparation of isopropenyl[1-oxido-4-(trifluoromethyl)pyridin-2-yl]carbamate

Isopropenyl [4-(trifluoromethyl)pyridin-2-yl]carbamate (1.2 g, 5.0 mmol)was suspended in CHCl₃ (20 mL) and treated with m-CPBA (841 mg, 5.0mmol). The reaction was stirred at rt overnight. The reaction wasquenched with satd. NaHCO₃ and extracted with CHCl₃. The organic layerwas dried (MgSO₄) and concentrated. The crude residue was purified oversilica using CH₂Cl₂ as the eluting solvent. An amber oil was collected(620 mg, 47%); ¹H-NMR (DMSO-d₆) δ 10.2 (s, 1H), 8.56 (d, J=6.9 Hz, 1H),8.25 (d, J=2.6 Hz, 1H), 7.52 (ddd, dd, J₁=6.8 Hz, J₂=2.5 Hz, J₃=0.6 Hz,1H), 4.85 (q, J=1.2 Hz, 1H), 4.80 (d, J=1.2 Hz, 1H), 1.94 (d, J=0.4 Hz,3H).

Step 3. Preparation of the Title Compound

The procedure used for the preparation of Example 2 was used to preparethe title compound by substituting isopropenyl[1-oxido-4-(trifluoromethyl)pyridin-2-yl]carbamate forphenyl(3-tert-butylisoxazol-5-yl)carbamate and5-(4-amino-3-methylphenyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-aminefor Intermediate E. ¹H-NMR (DMSO-d₆) δ 10.75 (s, 1H), 9.39 (s, 1H), 8.63(d, J=2.6 Hz, 1H), 8.57 (d, J=7.0 Hz, 1H), 7.92-7.90 (m, 2H), 7.42 (dd,J₁=6.0 Hz, J₂=2.3 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.28 (dd, J₁=8.2 Hz,J₂=1.7 Hz, 1H), 6.34 (s, 1H), 3.82 (s, 2H), 3.56 (t, J=4.6 Hz, 4H),2.47-2.41 (m, 4H), 1.98 (s, 3H); MS [M+H]⁺=515.1; LCMS RT=2.21 min.

Example 300N-{4-[4-amino-7-(morpholin-2-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 289 was used toprepare the title compound by substituting Intermediate Q forIntermediate O in step 4. ¹H-NMR (CD₃OD) δ 8.25 (t, J=8.3 Hz, 1H), 8.09(s, 1H), 7.97-7.95 (m, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.52-7.47 (m, 2H),7.37-7.28 (m, 3H), 5.26 (dd, J₁=9.8 Hz, J₁=2.6 Hz, 1H), 4.70-4.55 (bs,1H), 3.99 (dd, J₁=11 Hz, J₁=2.7 Hz, 1H), 3.83-3.75 (m, 1H), 2.90-2.85(m, 2H), 2.75 (dd, J₁=13 Hz, J₁=9.8 Hz, 1H); MS [M+H]⁺=575.1; LCMSRT=2.63 min.

Example 301N-{4-[4-amino-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea

The procedure used for the preparation of Example 289 and 276 was usedto prepare the title compound by substituting Intermediate Q forIntermediate O in step 4 of Example 289. ¹H-NMR (CD₃OD) δ 8.19 (t, J=8.6Hz, 1H), 7.96 (bs, 1H), 7.83 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.49 (t,J=7.8 Hz, 1H), 7.33-7.24 (m, 3H), 6.62 (s, 1H), 4.10-3.88 (m, 2H),3.70-3.61 (m, 1H), 3.20-3.08 (m 2H), 2.99 (dd, J₁=13 Hz, J₂=2.1 Hz, 1H),2.93-2.86 (m, 2H), 2.69 (dd, J₁=13 Hz, J₂=11 Hz, 1H); MS [M+H]⁺=530.2;LCMS RT=2.80 min.

Biological Evaluation

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) were demonstrated withthe use of in vitro tumor proliferation assays.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

FGFR-1TR-FRET Biochemical Assay

The FGFR-1 Assay was performed on half well 96-well opaque plates(Costar 3915) in a LANCE format. LANCE is a homogenous time resolvedfluormetry based application available through Perkin Elmer. For thisassay, 50 uL reactions were set up using: 0.6 uM ATP (Sigma), 25 nM polyGT-biotin (CIS BIO International), 2 nM Eu-labelled phospho-Tyr Ab (PY20PerkinElmer), 10 nM Streptavidin-APC (Perkin Elmer), 5 nM FGFR1-GST(generated by DRT, Bayer Healthcare), 1% DMSO, 50 mM HEPES pH 7.5, 10 mMMgCl2, 0.1 mM EDTA, 0.015% Brij, 0.1 mg/ml BSA, 0.1% B-mercaptoethanol.All reactions were initiated with the addition of enzyme and were leftto incubate for one hour at room temperature. Time-resolved fluorescencewas then read on a Perkin Elmer VictorV Multilabel counter. The readingprotocol uses an excitation wavelength at 340 nm and emission reads atboth 615 and 665 nm. Signal was calculated as a ratio: (Flourescence at665 nm/Flourescence at 615 nM)*10000 for each well. The backgroundcontrol used for this assay is the signal produced with all assaycomponents excluding ATP. For IC₅₀ generation, compounds were addedprior to the enzyme initiation. A 50-fold stock plate was made withcompounds serially diluted 1:5 in a 50% DMSO/50% dH2O solution. A 1 μLaddition of the stock to the assay wells gave final compoundconcentrations ranging from 10 μM-0.128 nM in 1% DMSO. The data wereexpressed as percent inhibition: % inhibition=100−((Signal withinhibitor−background)/(Signal without inhibitor−background))*100.

Tumor Cell Proliferation

Human tumor cells (e.g., HCT116 or MDA-MB-231 cells), were seeded in aCostar 96-well plate at 3.0×10³ cells/well and grown in 150 μl of RPMIcomplete media (Invitrogen Corporation, Grand Island, N.Y.) containing10% fetal bovine serum (Hyclone, Logan, Utah) at 37° C. for 16 h in anincubator with 5% CO₂. To each well, 50 μl of additional growth mediacontaining 40 μM to 18 nM concentrations of compound with 0.4% DMSO wasadded. Cells were grown for another 72 h at 37° C. with 5% CO₂. 20 μl ofAlamar Blue (Trek Diagnostic Systems, Inc., Cleveland, Ohio) reagent wasadded to each well and incubated for 3 h at 37° C. Plates were read in aSpectraMax Gemini (Molecular Devices, CA) with 544 nm excitation and 590nm emission wavelength. IC₅₀ values were determined by linear regressionanalysis of log drug concentration versus percent inhibition.

P-Histone3

Compounds were assayed for the inhibition of histone 3 phosphorylationin colon carcinoma (HCT116). Briefly, 20,000 cells/well were seeded in a96-well black-walled, poly-d-lysine plates in RPMI+10% FBS and incubatedat 37° C. in 5% CO₂ overnight. The following day, the cells were treatedwith compounds for 24 hours at 37° C. Following compound treatment;plates were centrifuged at 1000 rpm for 2 minutes and washed twice with100 μl of cold sterile TBS. Cells were then fixed with cold 3.7%formaldehyde in TBS (4° C. for 1 hour) and then permeabolized with 0.1%Triton-X-100 in TBS (room temperature for 30 minutes). Plates were thenwashed with of 0.25% BSA-TBS and blocked with BSA solution for 1 hour atroom temperature while shaking. The supernatant was removed and replacedwith diluted primary antibody (anti-phospho-histone 3, serine 10, CellSignaling) at 1:250 in 0.25% BSA-TBS and incubated overnight at 4° C.The plates were washed and treated with diluted secondary antibody(anti-rabbit Eu-labeled) at 1:10000 in 0.25% BSA-TBS (room temperaturefor 1 hour). The antibody solution was removed from each well and washedeight times. The wash buffer was replaced with 50 μl pre-warmedenhancement solution and mixed on the orbital shaker for 10 minutes.Fluorescence was detected with a Victor V Fluorescence Detector. Thedata are expressed as percent inhibition: % inhibition=100−((Signal withinhibitor−background)/(Signal without inhibitor−background))−100.

In Vivo Efficacy Studies: Staged Human Xenograft Models

Staged human xenograft models grown in mice or rats were used toevaluate compound efficacy. To generate tumors, cells harvested frommid-log phase cultures or tumor fragments from in vivo passage wereinjected s.c. in the flank of athymic mice or rats. Treatmentadministered p.o. or i.v. was initiated when all mice in each experimenthad established tumors. The general health of animals was monitored andmortality was recorded daily. Tumor dimensions and body weights wererecorded two to three times a week starting with the first day oftreatment. Tumor weights were calculated using the equation (l×w2)/2,where l and w refer to the larger and smaller dimensions collected ateach measurement. Anti-tumor efficacy was measured as tumor growthinhibition (TGI). TGI is calculated by the equation [1−(T/C)*100], whereT and C represent the mean tumor size of the treated (T) and untreatedor vehicle control (C) groups, respectively, at the end of treatment.

In Vitro Soft Agar Assays Measuring Anchorage-Independent Growth:

One of the hallmarks of an oncogenically-transformed cell is its abilityto survive and proliferate in an anchorage-independent manner. Tomeasure this anchorage-independent growth, soft agar assays areperformed. A mixture of 1000 cells in 100 μl of growth medium containing0.36% agarose (supplemented with 10% (v/v) FBS) is plated onto 50 μl ofsolidified growth medium containing 0.6% (wlv) agarose in 96 wellplates. Once the cell/medium/agarose mixture have solidified, 50 μl ofgrowth medium is added to cover the wells and plates are incubatedovernight at 37° C. in a 5% CO₂ incubator. The following day, compoundsdiluted in growth media with a final concentration of DMSO not to exceed0.1% (v/v) are added to each well. Cells are further incubated for 5days at 37° C. in a humidified incubator containing 5% CO₂. On day 5, 40μl of MTS reagent (CellTiter 96 Aqueous One Solution, Promega, Madison,Wis.) is added to each well and the plates are incubated for anadditional 2 hours at 37° C. Plates are then read at 490 nm on aSpectraMax 250 plate reader (Molecular Devices, Sunnyvale, Calif.).

Percent inhibition is calculated using the following equation:

% inhibition=1−(T _(5test) −T ₀)/(T _(5control) −T ₀)×100.

T_(5test)=O.D. at 490 nm in the presence of test compound at day 5

T_(5control)=O.D. at 490 nm in the DMSO treated control cells at day 5

T₀=O.D. at 490 nm in the presence of compound at day 0

Apoptosis Assays: Cell Death Detection Assay to Measure DNAFragmentation

The Cell Death Detection ELISAPlus kit (Roche, Mannheim, Germany) isused to measure DNA fragmentation as a marker for apoptosis. Cells areseeded in 96-well plates at 10,000 cells/well and after 24 hr, are dosedand grown for an additional 48 hr in media containing 10% FBS in 5% CO₂at 37° C. Supernatants from control and treated cells are transferredinto streptavidin-coated 96-well plates and incubated with biotinylatedmouse anti-histone antibody and peroxidase-conjugated mouse anti-DNAantibody at room temperature for 2 hr. After the removal of unboundantibodies by washing, the amount of apoptosis-generated nucleosomes isquantified as the peroxidase retained in the immuno-complex using ABTS(2,2′-azino-di[3-ethylbenzthiazolin-sulfonate]) as the substrate.Absorbance is determined at 405-490 nm using a SpectraMax microplatereader (Molecular Devices, Sunnyvale, Calif.).

Apoptosis Assays: Caspase 3/7 Activation

Execution of cell death is dependent on caspase activity. Caspases 3/7are central executioners for apoptosis. Cells (10⁴ cells/well) areplated in 96-well microtiter plates and incubated in media containing10% FBS at 37° C. overnight in a humidified incubator containing 5% CO₂.On the following day, compounds are added to wells and cultures areincubated for an additional 24 hrs. Caspase 3/7 activity is measured byadding the profluorescent substrate, Z-DEVD-AFC(7-Amino-4-Triflourocoumarin; 75 μM; Calbiochemicals, San Diego,Calif.), freezing the plate, and then thawing the cells for 3 hours atroom temperature. Plates are read at 400 nm (excitation wavelength) and505 nm (emission wavelength) on a SpectraMax Gemini microplate reader(Molecular Devices, Sunnyvale, Calif.).

Compounds of the invention were tested for activity using the FGFR1biochemical, tumor cell proliferation and p-Histone3.

Compounds of examples 1, 2, 3, 4, 6, 8, 9, 11, 10, 12, 15, 16, 18, 19,20, 22, 25, 26, 27, 28, 29, 39, 40 41, 50, 52, 53, 65, 67, 75, 77, 78,79, 81, 89, 107, 108, 109, 111, 113, 114, 116, 119, 120, 121, 128, 129,149, 161, 163, 164, 165, 167, 168, 173, 176, 177, 179, 180, 181, 184,186, 187, 188, 189, 190, 191, 193, 194, 195, 201, 202, 203, 204, 205,206, 214, 219, 220, 221, 224, 226, 228, 236, 237, 240, 241, 242, 253,259, 269 and 287 demonstrate an IC₅₀ of less than 10 nM in the FGFR-1biochemical assay. Compounds of examples 21, 30, 31, 32, 33, 35, 36, 37,38, 42, 44, 58, 59, 66, 82, 83, 84, 85, 86, 100, 103, 104, 115, 124,133, 136, 145, 196, 200, 208, 209, 211, 212, 215, 216, 217, 230, 231,234, 235, 243, 250, 252, 255, 273, 276, 283, 284, 289, 293 and 301demonstrate an IC₅₀ greater than 10 nM but less than 100 nM in theFGFR-1 biochemical assay. Compounds of examples 7, 14, 49, 55, 57, 63,80, 112, 147, 198, 254 and 260 demonstrate an IC₅₀ greater than 100 nMbut less than 1 μM in FGFR-1 biochemical assay.

Compounds of examples 1, 3, 5, 6 and 8 demonstrate an IC₅₀ greater than500 nM but less than 4 μM in the H460 proliferation assay.

Compounds of examples 3, 4, 5 and 6 demonstrate an IC₅₀ greater than 500nM but less than 4 μM in the HCT116 proliferation assay.

Compounds of examples 3, 4, 5 and 6 demonstrate an IC₅₀ greater than 500nM but less than 3 μM in the MDA-MB-231 proliferation assay.

Compound of examples 4, 10, 15, 16, 25, 83, 87, 91, 93, 94, and 105demonstrate an IC₅₀ greater than 500 nM but less than 5 μM in thep-histone3 assay. Compounds of examples, 44, 46, 56, 72, 73, and 74demonstrate an IC₅₀ greater than 5 μM but less than 10 μM in thep-histone3 assay.

1. A compound of formula (I)

wherein X⁰ represents C or N; R¹ represents 1.1) phenyl or a bicyclic carbocycle of 9-10 ring members, in which at least one ring is aromatic, R¹ optionally bearing up to 4 substituents independently selected from the group consisting of 1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.1.a1) halogen; 1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(7a) wherein R^(7a) represents H or (C₁-C₃)alkyl, or R⁶ and R⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl; and 1.1.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.1.b1) halogen; and 1.1.b2) OR⁹ wherein R⁹ represents H or (C₁-C₃)alkyl which may optionally bear halogen or (C₁-C₃)mono- or di-alkylamino; 1.1.c) OR¹⁰ wherein R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.1.c1) halogen; 1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl which may optionally bear (C₁-C₃)mono- or di-alkylamino; and 1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹² and R¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl; 1.1.d) —C(O)—OR¹⁵ wherein R¹⁵ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; 1.1.e) —C(O)—NR¹⁶R¹⁷ wherein R¹⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.1.e1) halogen; 1.1.e2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.1.e3) phenyl; 1.1.e4) —SO₂CH₃; 1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁹ and R²⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl; 1.1.f) —N(R²²)—C(O)—R²³ wherein R²² represents H or (C₁-C₃)alkyl; and R²³ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.1.f1) optionally substituted phenyl, 1.1.f2) OR²⁴ wherein R²⁴ represents H or (C₁-C₃)alkyl, or 1.1.f3) NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R²⁵ and R²⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²⁷ wherein R²⁷ represents H or (C₁-C₃)alkyl; 1.1.g) —SO₂NR²⁸R²⁹ wherein R²⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R²⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with: 1.1.g1) halogen; 1.1.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.1.g3) phenyl; 1.1.g4) —SO₂CH₃; 1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R³¹ and R³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl; 1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein R³⁴ represents H or (C₁-C₃)alkyl, and R³⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.1.h1) halogen; 1.1.h2) optionally substituted phenyl, 1.1.h3) OR³⁶ wherein R³⁶ represents H or (C₁-C₃)alkyl, or 1.1.h4) NR³⁷R³⁸ wherein R³⁷ and R³⁸ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R³⁷ and R³⁸ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³⁹ wherein R³⁹ represents H or (C₁-C₃)alkyl; 1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl; 1.1.j) halogen; 1.1.k) optionally substituted phenyl; 1.1.l) NO₂; 1.1.m) CN; and 1.1.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.1.o) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; or R¹ represents 1.2) a 5-6 membered aromatic heterocycle containing up to 3 heteroatoms independently selected from the group consisting of N, O, and S; or a bicyclic heterocycle of 8-10 ring members in which at least one ring is aromatic and contains up to 3 moieties independently selected from the group consisting of N, N→O, O, and S, and any non-aromatic ring of said bicyclic heterocycle optionally contains up to three moieties independently selected from the group consisting of O, S, S(O), S(O)₂, and NR⁴⁴ wherein R⁴⁴ represents H or —(C₁-C₃)alkyl; said R¹ heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of 1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.2.a1) halogen; 1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(47a) wherein R^(17a) represents H or (C₁-C₃)alkyl, or R⁴⁶ and R⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and 1.2.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.2.b1) halogen; and 1.2.b2) OR⁴⁹ wherein R⁴⁹ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 1.2.c) OR⁵⁰ wherein R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or —(C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.2.c1) halogen; 1.2.c2) OR⁵¹ wherein R⁵¹ represents H or (C₁-C₃)alkyl which may optionally bear —(C₁-C₃)mono- or di-alkylamino; and 1.2.c3) —NR⁵²R⁵¹ in which R⁵² and R⁵³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁵² and R⁵³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁵⁴ wherein R⁵⁴ represents H or (C₁-C₃)alkyl; 1.2.d) —C(O)—OR⁵⁵ wherein R⁵⁵ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; 1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.e1) halogen; 1.2.e2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.2.e3) phenyl; 1.2.e4) —SO₂CH₃; 1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.2.e6) —NR⁵⁹R⁶⁰ in which R⁵⁹ and R⁶⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁵⁹ and R⁶⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁶¹ wherein R⁶¹ represents H or (C₁-C₃)alkyl; 1.2.f) —N(R⁶²) —C(O)—R⁶³ wherein R⁶² represents H or (C₁-C₃)alkyl; and R⁶³ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.2.f1) optionally substituted phenyl, 1.2.f2) OR⁶⁴ wherein R⁶⁴ represents H or (C₁-C₃)alkyl, or 1.2.f3) NR⁶⁵R⁶⁶ wherein R⁶⁵ and R⁶⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁶⁵ and R⁶⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁶⁷ wherein R⁶⁷ represents H or (C₁-C₃)alkyl; 1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.g1) halogen; 1.2.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.2.g3) phenyl; 1.2.g4) —SO₂CH₃; 1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.2.g6 —NR⁷¹R⁷² in which R⁷¹ and R⁷² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁷¹ and R⁷² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁷³ wherein R⁷³ represents H or (C₁-C₃)alkyl; 1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein R⁷⁴ represents H or (C₁-C₃)alkyl, and R⁷⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.2.h1) halogen; 1.2.h2) optionally substituted phenyl, 1.2.h3) OR⁷⁶ wherein R⁷⁶ represents H or (C₁-C₃)alkyl, or 1.2.h4) NR⁷⁷R⁷⁸ wherein R⁷⁷ and R⁷⁸ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁷⁷ and R⁷⁸ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁷⁹ wherein R⁷⁹ represents H or (C₁-C₃)alkyl; 1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl; 1.2.j) halogen; 1.2.k) optionally substituted phenyl; 1.2.l) NO₂; 1.2.m) CN; and 1.2.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; R² represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R⁴ represents 4.1) —(C₁-C₅)alkyl which is optionally substituted with 4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl; 4.1.b) -halogen; 4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.c1) halogen; 4.1.c2) phenyl; 4.1.c3) —S(O)₂CH₃; 4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹² and R¹¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴ represents H or (C₁-C₃)alkyl; 4.1.d) —NR¹¹⁵R¹¹⁶ wherein R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.d1) halogen; 4.1.d2) —S(O)₂CH₃; 4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl; 4.1.e) optionally substituted phenyl; or 4.1.f) a 5-6 membered aromatic heterocycle containing up to two heteroatoms selected from O, S, and N; 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl; d represents 1, 2, or 3; e represents 0 or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl; g represents 1, 2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents 4.4.a) H; 4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in turn is optionally substituted with halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally substituted phenyl, or —(C₁-C₃)alkyl which may optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or (C₁-C₃)alkyl; 4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents 4.4.d1) optionally substituted phenyl, 4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.4.d2.1) halogen; 4.4.d2.2) optionally substituted phenyl; 4.4.d2.3) —S(O)₂—(C₁-C₄)alkyl which may optionally bear halogen; 4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or (C₁-C₄)alkyl which may optionally bear halogen; and 4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³¹ and R¹³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl; 4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl; and j represents 1, 2, or 3; 4.5)

wherein X represents C or N; R¹³⁸ represents 4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 4.5.a1) halogen; 4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are independently H or —(C₁-C₃)allyl which may optionally bear halogen or OR^(141a) wherein R^(141a) represents H or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴² wherein R¹⁴² represents H or (C₁-C₃)alkyl; and 4.5.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 4.5.b1) halogen; and 4.5.b2) OR¹⁴³ wherein R¹⁴³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.5.c) OR¹⁴⁴ wherein R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 4.5.c1) halogen; 4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear (C₁-C₃)mono- or di-alkylamino; and 4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴¹ wherein R¹⁴⁸ represents H or (C₁-C₃)alkyl; 4.5.d) —C(O)—OR¹⁴⁹ wherein R¹⁴⁹ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3.halogens; 4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.e1) halogen; 4.5.e2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 4.5.e3) phenyl; 4.5.e4) —SO₂CH₃; 4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl; 4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein R¹⁵⁶ represents H or (C₁-C₃)alkyl; and R¹⁵⁷ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.f 1) optionally substituted phenyl, 4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl, or 4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁶¹ wherein R¹⁶¹ represents H or (C₁-C₃)alkyl; 4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein R¹⁶² represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.g1) halogen; 4.5.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 4.5.g3) phenyl; 4.5.g4) —SO₂CH₃; 4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl; 4.5.h) —N(R⁶⁸)—SO₂—R¹⁶⁹ wherein R¹⁶⁸ represents H or (C₁-C₃)alkyl, and R¹⁶⁹ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.h1) halogen, 4.5.h2) optionally substituted phenyl, 4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen, or 4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷³ wherein R¹⁷³ represents H or (C₁-C₃)alkyl; 4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl; 4.5.j) halogen; 4.5.k) optionally substituted phenyl; 4.5.l) NO₂; 4.5.m) CN; or 4.5.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; and k represents 0, 1, or 2; 4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3; 4.7)

wherein n represents 1, 2, or 3; and p represents 0, 1, or 2; 4.8)

wherein q represents 1, 2, or 3; 4.9)

wherein R¹⁷⁸ represents 4.9.a) H; 4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally substituted with halogen; 4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen; 4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen; 4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally substituted phenyl or —(C₁-C₃)alkyl, which may be substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.9.f1) halogen; 4.9.f2) optionally substituted phenyl; 4.9.f3) —S(O)₂CH₃; 4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(185a) wherein R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl; 4.9g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or 4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each independently represents H or —(C₁-C₄)alkyl which may optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl; r represents 0, 1, or 2; and s represents 0 or 1; 4.10)

wherein R¹⁹¹ represents 4.10.a) H; 4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl; 4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or —(C₁-C₃)alkyl, both of which may be substituted with halogen or —(C₁-C₃)alkyl; 4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.10.d1) halogen; 4.10.d2) phenyl; 4.10.d3) —S(O)₂CH₃; 4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(197a) wherein R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl; 4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or 4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²⁰² wherein R²⁰² represents H or (C₁-C₃)alkyl; and X represents O, S, S(O), S(O)₂, or NR²⁰³ wherein R²⁰³ represents H or —(C₁-C₃)alkyl; and t represents 0, 1, or 2; 4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.11.a) halogen; 4.11.b) optionally substituted phenyl; 4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.11.d)

4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O and S, said alkyl or ring optionally bearing up to 3 substituents independently selected from 4.12.a) halogen; 4.12.b) optionally substituted phenyl; 4.12.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.12.d)

4.13) halogen; or 4.14) CN; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 wherein in formula (I) wherein:

X⁰ represents C or N; R¹ represents 1.1) phenyl which may optionally bear up to 4 substituents independently selected from the group consisting of 1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.1.a1) halogen; 1.1.a2) OR⁵ wherein R⁵ represents H or (C_(l)-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(7a) wherein R^(7a) represents H or (C₁-C₃)alkyl, or R⁶ and R⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl; and 1.1.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.1.b1) halogen; 1.1.c) OR¹⁰ wherein R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.1.c1) halogen; 1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl which may optionally bear (C₁-C₃)mono- or di-alkylamino; and 1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹² and R¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl; 1.1.e) —C(O)—NR¹⁶R¹⁷ wherein R¹⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.1.e1) halogen; 1.1.e3) phenyl; 1.1.e4) —SO₂CH₃; 1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁹ and R²⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl; 1.1.f) —N(R²²)—C(O)—R²³ wherein R²² represents H or (C₁-C₃)alkyl; and R²³ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.1.f1) optionally substituted phenyl, 1.1.f2) OR²⁴ wherein R²⁴ represents H or (C₁-C₃)alkyl, or 1.1.f3) NR²⁵R²⁶ wherein R²⁵ and R²⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R²⁵ and R²⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²⁷ wherein R²⁷ represents H or (C₁-C₃)alkyl; 1.1.g) —SO₂NR²⁸R²⁹ wherein R²⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R²⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with: 1.1.g1) halogen; 1.1.g3) phenyl; 1.1.g4) —SO₂CH₃; 1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R³¹ and R³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl; 1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein R³⁴ represents H or (C₁-C₃)alkyl, and R³⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.1.h1) halogen; 1.1.h2) optionally substituted phenyl, 1.1.h3) OR³⁶ wherein R³⁶ represents H or (C₁-C₃)alkyl, or 1.1.h4) NR³⁷R³⁸ wherein R³⁷ and R³⁸ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R³⁷ and R³⁸ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³⁹ wherein R³⁹ represents H or (C₁-C₃)alkyl; 1.1.i) —NR⁴⁰OR⁴¹ in which R⁴⁰ and R⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl; 1.1.j) halogen; 1.1.l) NO₂; 1.1.m) CN; and 1.1.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.1.o) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; or R¹ represents 1.2) a 5-6 membered aromatic heterocycle containing up to 3 heteroatoms independently selected from-the group consisting of N, O, and S; said R¹ heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of 1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.2.a1) halogen; 1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(47a) wherein R^(47a) represents H or (C₁-C₃)alkyl, or R⁴⁶ and R⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and 1.2.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.2.b1) halogen; 1.2.c) OR⁵⁰ wherein R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or —(C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.2.c1) halogen; 1.2.c2) OR⁵¹ wherein R⁵¹ represents H or (C₁-C₃)alkyl which may optionally bear —(C₁-C₃)mono- or di-alkylamino; and 1.2.c3) —NR⁵²R⁵³ in which R⁵² and R⁵³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁵² and R⁵³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁵⁴ wherein R⁵⁴ represents H or (C₁-C₃)alkyl; 1.2.e) —C(O)—NR⁵⁶R⁵⁷ wherein R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.e1) halogen; 1.2.e3) phenyl; 1.2.e4) —SO₂CH₃; 1.2.e5) —OR⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.2.e6) —NR⁵⁹R⁶⁰ in which R⁵⁹ and R⁶⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁵⁹ and R⁶⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁶¹ wherein R⁶¹ represents H or (C₁-C₃)alkyl; 1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein R⁶² represents H or (C₁-C₃)alkyl; and R⁶³ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.2.f1) optionally substituted phenyl, 1.2.f2) OR⁶⁴ wherein R⁶⁴ represents H or (C₁-C₃)alkyl, or 1.2.f3) NR⁶⁵R⁶⁶ wherein R⁶⁵ and R⁶⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁶⁵ and R⁶⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁶⁷ wherein R⁶⁷ represents H or (C₁-C₃)alkyl; 1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁶⁹ represents H or 13 (C₁-C₄)alkyl which is optionally substituted with 1.2.g1) halogen; 1.2.g3) phenyl; 1.2.g4) —SO₂CH₃; 1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.2.g6 —NR⁷¹R⁷² in which R⁷¹ and R⁷² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁷¹ and R⁷² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁷³ wherein R⁷³ represents H or (C₁-C₃)alkyl; 1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein R⁷⁴ represents H or (C₁-C₃)alkyl, and R⁷⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.2.h1) halogen; 1.2.h2) optionally substituted phenyl, 1.2.h3) OR⁷⁶ wherein R⁷⁶ represents H or (C₁-C₃)alkyl, or 1.2.h4) NR⁷⁷R⁷⁸ wherein R⁷⁷ and R⁷⁸ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁷⁷ and R⁷⁸ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁷⁹ wherein R⁷⁹ represents H or (C₁-C₃)alkyl; 1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl; 1.2.j) halogen; 1.2.k) optionally substituted phenyl; 1.2.l) NO₂; 1.2.m) CN; and 1.2.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; R² represents halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R⁴ represents 4.1) —(C₁-C₅)alkyl which is optionally substituted with 4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl; 4.1.b) -halogen; 4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.c1) halogen; 4.1.c2) phenyl; 4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹² and R¹¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴ represents H or (C₁-C₃)alkyl; 4.1.d) —NR¹¹⁵R¹¹⁶ wherein R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.d1) halogen; 4.1.d2) —S(O)₂CH₃; 4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl; or 4.1.f) a 5-6 membered aromatic heterocycle containing up to two heteroatoms selected from O, S, and N; 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl; d represents 1, 2, or 3; e represents 0or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl; g represents 1, 2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents 4.4.a) H; 4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in turn is optionally substituted with halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally substituted phenyl, or —(C₁-C₃)alkyl which may optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or (C₁-C₃)alkyl; 4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents 4.4.d1) optionally substituted phenyl, 4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.4.d2.1) halogen; 4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³¹ and R¹³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl; 4.4.d3) OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl which may optionally bear halogen; or 4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl; and j represents 1, 2, or 3; 4.5)

wherein X represents C or N; R¹³⁸ represents 4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 4.5.a1) halogen; 4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(141a) wherein R^(141a) represents H or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴² wherein R¹⁴² represents H or (C₁-C₃)alkyl; and 4.5.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 4.5.b1) halogen; 4.5.c) OR¹⁴⁴ wherein R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 4.5.c1) halogen; 4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear (C₁-C₃)mono- or di-alkylamino; and 4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸ represents H or (C₁-C₃)alkyl; 4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.e1) halogen; 4.5.e3) phenyl; 4.5.e4) —SO₂CH₃; 4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl; 4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein R¹⁵⁶ represents H or (C₁-C₃)alkyl; and R¹⁵⁷ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.f1) optionally substituted phenyl, 4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl, or 4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹ represents H or (C₁-C₃)alkyl; 4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein R¹⁶² represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.g1) halogen; 4.5.g3) phenyl; 4.5.g4) —SO₂CH₃; 4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl; 4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein R¹⁶⁸ represents H or (C₁-C₃)alkyl, and R¹⁶⁹ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.h1) halogen, 4.5.h2) optionally substituted phenyl, 4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen, or 4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷³ wherein R¹⁷³ represents H or (C₁-C₃)alkyl; 4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl; 4.5.j) halogen; 4.5.l) NO₂; 4.5.m) CN; or 4.5.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; and k represents 0, 1, or 2; 4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3; 4.7)

wherein n represents 1, 2, or 3; and p represents 0, 1, or 2; 4.8)

wherein q represents 1, 2, or 3; 4.9)

wherein R¹⁷⁸ represents 4.9.a) H; 4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally substituted with halogen; 4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen; 4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen; 4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally substitutued phenyl or —(C₁-C₃)alkyl, which may be substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H or (C₁-C₃)alkyl which may -optionally bear halogen; 4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.9.f1) halogen; 4.9.f2) optionally substituted phenyl; 4.9.f3) —S(O)₂CH₃; 4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(185a) wherein R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl; 4.9g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or 4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each independently represents H or —(C₁-C₄)alkyl which may optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl; r represents 0, 1, or 2; and s represents 0 or 1; 4.10)

wherein R¹⁹¹ represents 4.10.a) H; 4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl; 4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or —(C₁-C₃)alkyl, both of which may be substituted with halogen or —(C₁-C₃)alkyl; 4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.10.d1) halogen; 4.10.d2) phenyl; 4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(197a) wherein R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl; 4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or 4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²⁰² wherein R²⁰² represents H or (C₁-C₃)alkyl; and X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H or —(C₁-C₃)alkyl; and t represents 0, 1, or 2; 4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.11.a) halogen; 4.11.b) optionally substituted phenyl; 4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.11.d)

4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O and S, said alkyl or ring optionally bearing up to 3 substituents independently selected from 4.12.a) halogen; 4.12.b) optionally substituted phenyl; 4.12.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.12.d)

4.13) halogen; or 4.14) CN; or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 1 wherein in formula (I)

wherein: X⁰ represents C; R¹ represents 1.1) phenyl which may optionally bear up to 4 substituents independently selected from the group consisting of 1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.1.a1) halogen; 1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or R⁶ and R⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl; and 1.1.a4) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.1.b1) halogen; 1.1.c) OR¹⁰ wherein R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.1.c1) halogen; 1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl; and 1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹² and R¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl; 1.1.e) —C(O)—NR¹⁶R¹⁷ wherein R¹⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.1.e1) halogen; 1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁹ and R²⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl; 1.1.f) —N(R²²)—C(O)—R²³ wherein R²² represents H or (C₁-C₃)alkyl; and R²³ represents optionally substituted phenyl, or (C₁-C₄)alkyl; 1.1.g) —SO₂NR²⁸R²⁹ wherein R²⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R²⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with: 1.1.g1) halogen; 1.1.g4) —SO₂CH₃; 1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R³¹ and R³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl; 1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein R³⁴ represents H or (C₁-C₃)alkyl, and R³⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.1.h1) halogen; 1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³ wherein R⁴³ represents H or (C₁-C₃)alkyl; 1.1.j) halogen; 1.1.l) NO₂; 1.1.m) CN; and 1.1.n) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.1.o) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; or R¹ represents 1.2) a 5-6 membered aromatic heterocycle selected from imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, and furan; said R¹ heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of 1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.2.a1) halogen; 1.2.a2) OR⁴⁴ wherein R⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁴⁶ and R⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and 1.2.a4) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.2.b1) halogen; 1.2.c) OR⁵⁰ wherein R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or —(C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.2.c1) halogen; 1.2.e) —C(O)—NR⁵⁶R⁵⁷wherein R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.e1) halogen; or 1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein R⁶² represents H or (C₁-C₃)alkyl; and R⁶³ represents optionally substituted phenyl, or (C₁-C₄)alkyl; 1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.g1) halogen; or 1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.2.h) —N(⁷⁴)—SO₂—R⁷⁵ wherein R⁷⁴ represents H or (C₁-C₃)alkyl, and R⁷⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.2.h1) halogen; 1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl; 1.2.j) halogen; 1.2.k) optionally substituted phenyl; 1.2.1) NO₂; 1.2.m) CN; and 1.2.n) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; R² represents halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R⁴ represents 4.1) —(C₁-C₅)alkyl which is optionally substituted with 4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl; 4.1.b) -halogen; 4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.c1) halogen; 4.1.c2) phenyl; 4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹² and R¹¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴ represents H or (C₁-C₃)alkyl; 4.1.d) —NR¹¹⁵R¹¹⁶ wherein R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.d1) halogen; 4.1.d2) —S(O)₂CH₃; 4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl; or 4.1.f) a 5-6 membered aromatic heterocycle containing up to two heteroatoms selected from O, S, and N; 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl; d represents 1, 2, or 3; e represents 0 or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl; g represents 1, 2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents 4.4.a) H; 4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in turn is optionally substituted with halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally substituted phenyl, or —(C₁-C₃)alkyl which may optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or (C₁-C₃)alkyl; 4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents 4.4.d1) optionally substituted phenyl, 4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.4.d2.1) halogen; 4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³¹ and R¹³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl; 4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl which may optionally bear halogen; or 4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl; and j represents 1, 2, or 3; 4.5)

wherein X represents C or N; R¹³⁸ represents 4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 4.5.a1) halogen; 4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 4.5.a3) 13 NR¹⁴⁰R¹⁴¹ in which R¹⁷⁴⁰ and R¹⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(141a) wherein R^(141a) represents H or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴² wherein R¹⁴² represents H or (C₁-C₃)alkyl; and 4.5.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 4.5.b1) halogen; 4.5.c) OR¹⁴⁴ wherein R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 4.5.c1) halogen; 4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear (C₁-C₃)mono- or di-alkylamino; and 4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸ represents H or (C₁-C₃)alkyl; 4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.e1) halogen; 4.5.e3) phenyl; 4.5.e4) —SO₂CH₃; 4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl; 4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein R¹⁵⁶ represents H or (C₁-C₃)alkyl; and R¹⁵⁷ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.f1) optionally substituted phenyl, 4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl, or 4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹ represents H or (C₁-C₃)alkyl; 4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein R¹⁶² represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.g1) halogen; 4.5.g3) phenyl; 4.5.g4) —SO₂CH₃; 4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl; 4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein R¹⁶⁸represents H or (C₁-C₃)alkyl, and R¹⁶⁹ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.h1) halogen, 4.5.h2) optionally substituted phenyl, 4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen, or 4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷³ wherein R¹⁷³ represents H or (C₁-C₃)alkyl; 4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl; 4.5.j) halogen; 4.5.l)NO₂; 4.5.m) CN; or 4.5.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; and k represents 0, 1, or 2; 4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3; 4.7)

wherein n represents 1, 2, or 3; and p represents 0, 1, or 2; 4.8)

wherein q represents 1, 2, or 3; 4.9)

wherein R¹⁷⁸ represents 4.9.a) H; 4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally substituted with halogen; 4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen; 4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen; 4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally substitutued phenyl or —(C₁-C₃)alkyl, which may be substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.9.f1) halogen; 4.9.f2) optionally substituted phenyl; 4.9.f3) —S(O)₂CH₃; 4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(185a) wherein R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl; 4.9.g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or 4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each independently represents H or —(C₁-C₄)alkyl which may optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl; r represents 0, 1, or 2; and s represents 0 or 1; 4.10)

wherein R¹⁹¹ represents 4.10.a) H; 4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl; 4.10.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or —(C₁-C₃)alkyl, both of which may be substituted with halogen or —(C₁-C₃)alkyl; 4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.10.d1) halogen; 4.10.d2) phenyl; 4.10.d4) OR¹⁹⁴ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(197a) wherein R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl; 4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or 4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²⁰² wherein R²⁰² represents H or (C₁-C₃)alkyl; and X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H or —(C₁-C₃)alkyl; and t represents 0, 1, or 2; 4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.11.a) halogen; 4.11.b) optionally substituted phenyl; 4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.11.d)

4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O and S, said alkyl or ring optionally bearing up to 3 substituents independently selected from 4.12.a) halogen; 4.12.b) optionally substituted phenyl; 4.12.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.12.d)

4.13) halogen; or 4.14) CN; or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 1 wherein in formula (I)

wherein: X⁰ represents C; R¹ represents 1.1) phenyl which may optionally bear up to 4 substituents independently selected from the group consisting of 1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.1.a1) halogen; 1.1.a2) OR⁵ wherein R⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.1.a3) —NR⁶R⁷ in which R⁶ and R⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or R⁶ and R⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸ wherein R⁸ represents H or (C₁-C₃)alkyl; and 1.1.a4) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.1.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.1.b1) halogen; 1.1.c) OR¹⁰ wherein R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.1.c1) halogen; 1.1.c2) OR¹¹ wherein R¹¹ represents H or (C₁-C₃)alkyl; and 1.1.c3) NR¹²R¹³ in which R¹² and R¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹² and R¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴ wherein R¹⁴ represents H or (C₁-C₃)alkyl; 1.1.e) —C(O)—NR¹⁶R¹⁷ wherein R¹⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.1.e1) halogen; 1.1.e5) —OR¹⁸ wherein R¹⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.e6) —NR¹⁹R²⁰ in which R¹⁹ and R²⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁹ and R²⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²¹ wherein R²¹ represents H or (C₁-C₃)alkyl; 1.1.f) —N(R²²)—C(O)—R²³ wherein R²² represents H or (C₁-C₃)alkyl; and R²³ represents optionally substituted phenyl, or (C₁-C₄)alkyl; 1.1.g) —SO₂NR²⁸R²⁹ wherein R²⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R²⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with: 1.1.g1) halogen; 1.1.g4) —SO₂CH₃; 1.1.g5) —OR³⁰ wherein R³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 1.1.g6) —NR³¹R³² in which R³¹ and R³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R³¹ and R³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR³³ wherein R³³ represents H or (C₁-C₃)alkyl; 1.1.h) —N(R³⁴)—SO₂—R³⁵ wherein R³⁴ represents H or (C₁-C₃)alkyl, and R³⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.1.h1) halogen; 1.1.i) —NR⁴⁰R⁴¹ in which R⁴⁰ and R⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR⁴² in which R⁴² represents H or (C₁-C₃)alkyl, or R⁴⁰ and R⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴³ wherein R⁴³ represents H or (C₁-C₃)alkyl; 1.1.j) halogen; 1.1.l) NO₂; 1.1.m) CN; and 1.1.n) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.1.o) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; or R¹ represents 1.2) a 5-6 membered aromatic heterocycle selected from imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, and furan; said R¹ heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of 1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 1.2.a1) halogen; 1.2.a2) OR⁴⁵ wherein R⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.2.a3) —NR⁴⁶R⁴⁷ in which R⁴⁶ and R⁴⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R⁴⁶ and R⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁴⁸ wherein R⁴⁸ represents H or (C₁-C₃)alkyl; and 1.2.a4) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.2.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 1.2.b1) halogen; 1.2.c) OR⁵⁰ wherein R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or —(C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 1.2.c1) halogen; 1.2.e) —C(O)—NR⁵⁶R⁵⁷wherein R⁵⁶ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁵⁷ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.e1) halogen; or 1.2.e5) —OR⁵⁸ wherein R⁵⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.2.f) —N(R⁶²)—C(O)—R⁶³ wherein R⁶² represents H or (C₁-C₃)alkyl; and R⁶³ represents optionally substituted phenyl, or (C₁-C₄)alkyl; 1.2.g) —SO₂NR⁶⁸R⁶⁹ wherein R⁶⁸ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R⁶⁹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 1.2.g1) halogen; or 1.2.g5) —OR⁷⁰ wherein R⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 1.2.h) —N(R⁷⁴)—SO₂—R⁷⁵ wherein R⁷⁴ represents H or (C₁-C₃)alkyl, and R⁷⁵ represents optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 1.2.h1) halogen; 1.2.i) —NR⁸⁰R⁸¹ in which R⁸⁰ and R⁸¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(81a) wherein R^(81a) represents H or (C₁-C₃)alkyl, or R⁸⁰ and R⁸¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR⁸² wherein R⁸² represents H or (C₁-C₃)alkyl; 1.2.j) halogen; 1.2.k) optionally substituted phenyl; 1.2.l) NO₂; 1.2.m) CN; and 1.2.n) an imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, or furan; 1.2.o) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; R² represents halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R⁴ represents 4.1) —(C₁-C₅)alkyl which is optionally substituted with 4.1.a) —(C₃-C₅)cycloalkyl which may optionally bear halogen or OR¹⁰⁹ wherein R¹⁰⁹ represents H or (C₁-C₃)alkyl; 4.1.b) -halogen; 4.1.c) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.c1) halogen; 4.1.c2) phenyl; 4.1.c4) OR¹¹¹ wherein R¹¹¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.c5) —NR¹¹²R¹¹³ in which R¹¹² and R¹¹³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹² and R¹¹³ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹¹⁴ wherein R¹¹⁴ represents H or (C₁-C₃)alkyl; 4.1.d) —NR¹¹⁵R¹¹⁶ wherein R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.d1) halogen; 4.1.d2) —S(O)₂CH₃; 4.1.d3) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.1.d4) —NR¹¹⁸R¹¹⁹ in which R¹¹⁸ and R¹¹⁹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹¹⁸ and R¹¹⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹²⁰ wherein R¹²⁰ represents H or (C₁-C₃)alkyl; or 4.1.f) a 5-6 membered aromatic heterocycle containing up to two heteroatoms selected from O, S, and N; 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²² in which R¹²² represents H or —(C₁-C₃)alkyl; d represents 1, 2, or 3; e represents 0 or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹²⁴ in which R¹²⁴ represents H or —(C₁-C₃)alkyl; g represents 1, 2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents 4.4.a) H; 4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen or, —OR¹²⁶ in which R¹²⁶ represents H or —(C₁-C₃)alkyl which in turn is optionally substituted with halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally substituted phenyl, or —(C₁-C₃)alkyl which may optionally bear halogen or OR¹²⁸ wherein R¹²⁸ represents H or (C₁-C₃)alkyl; 4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents 4.4.d1) optionally substituted phenyl, 4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.4.d2.1) halogen; 4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.4.d2.5) —NR¹³¹R¹³² in which R¹³¹ and R¹³² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³¹ and R¹³² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³³ wherein R¹³³ represents H or (C₁-C₃)alkyl; 4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl which may optionally bear halogen; or 4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹³⁵ and R¹³⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹³⁷ wherein R¹³⁷ represents H or (C₁-C₃)alkyl; and j represents 1, 2, or 3; 4.5)

wherein X represents C or N; R¹³⁸ represents 4.5.a) (C₁-C₄)alkyl, which may optionally bear up to 3 substituents independently selected from 4.5.a1) halogen; 4.5.a2) OR¹³⁹ wherein R¹³⁹ represents H or (C₁-C₃)alkyl which may optionally bear halogen or —(C₁-C₃)mono- or di-alkylamino; 4.5.a3) —NR¹⁴⁰R¹⁴¹ in which R¹⁴⁰ and R¹⁴¹ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(141a) wherein R^(141a) represents H or (C₁-C₃)alkyl, or R¹⁴⁰ and R¹⁴¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴² wherein R¹⁴² represents H or (C₁-C₃)alkyl; and 4.5.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; 4.5.b) —(C₃-C₆)cycloalkyl which may optionally bear up to 2 substituents independently selected from 4.5.b1) halogen; 4.5.c) OR¹⁴⁴ wherein R¹⁴⁴ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 substituents independently selected from 4.5.c1) halogen; 4.5.c2) OR¹⁴⁵ wherein R¹⁴⁵ represents H or (C₁-C₃)alkyl which may optionally bear (C₁-C₃)mono- or di-alkylamino; and 4.5.c3) NR¹⁴⁶R¹⁴⁷ in which R¹⁴⁶ and R¹⁴⁷³ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁴⁶ and R¹⁴⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁴⁸ wherein R¹⁴⁸ represents H or (C₁-C₃)alkyl; 4.5.e) —C(O)—NR¹⁵⁰R¹⁵¹ wherein R¹⁵⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁵¹ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.e1) halogen; 4.5.e3) phenyl; 4.5.e4) —SO₂CH₃; 4.5.e5) —OR¹⁵² wherein R¹⁵² represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.e6) —NR¹⁵³R¹⁵⁴ in which R¹⁵³ and R¹⁵⁴ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵³ and R¹⁵⁴ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁵⁵ wherein R¹⁵⁵ represents H or (C₁-C₃)alkyl; 4.5.f) —N(R¹⁵⁶)—C(O)—R¹⁵⁷ wherein R¹⁵⁶ represents H or (C₁-C₃)alkyl; and R¹⁵⁷ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.f1) optionally substituted phenyl, 4.5.f2) OR¹⁵⁸ wherein R¹⁵⁸ represents H or (C₁-C₃)alkyl, or 4.5.f3) NR¹⁵⁹R¹⁶⁰ wherein R¹⁵⁹ and R¹⁶⁰ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁵⁹ and R¹⁶⁰ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶¹ wherein R¹⁶¹ represents H or (C₁-C₃)alkyl; 4.5.g) —SO₂NR¹⁶²R¹⁶³ wherein R¹⁶² represents H or (C₁-C₃)alkyl which may optionally bear halogen; and R¹⁶³ represents H or —(C₁-C₄)alkyl which is optionally substituted with 4.5.g1) halogen; 4.5.g3) phenyl; 4.5.g4) —SO₂CH₃; 4.5.g5) —OR¹⁶⁴ wherein R¹⁶⁴ represents H or (C₁-C₃)alkyl which may optionally bear halogen; or 4.5.g6) —NR¹⁶⁵R¹⁶⁶ in which R¹⁶⁵ and R¹⁶⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁶⁵ and R¹⁶⁶ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁶⁷ wherein R¹⁶⁷ represents H or (C₁-C₃)alkyl; 4.5.h) —N(R¹⁶⁸)—SO₂—R¹⁶⁹ wherein R¹⁶⁸ represents H or (C₁-C₃)alkyl, and R¹⁶⁹ represents H, optionally substituted phenyl, or (C₁-C₄)alkyl which is optionally substituted with 4.5.h1) halogen, 4.5.h2) optionally substituted phenyl, 4.5.h3) OR¹⁷⁰ wherein R¹⁷⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen, or 4.5.h4) NR¹⁷¹R¹⁷² wherein R¹⁷¹ and R¹⁷² are independently H or —(C₁-C₃)alkyl which may optionally bear halogen, or R¹⁷¹ and R¹⁷² may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷³ wherein R¹⁷³ represents H or (C₁-C₃)alkyl; 4.5.i) —NR¹⁷⁴R¹⁷⁵ in which R¹⁷⁴ and R¹⁷⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(175a) wherein R^(175a) represents H or (C₁-C₃)alkyl, or R¹⁷⁴ and R¹⁷⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁷⁶ wherein R¹⁷⁶ represents H or (C₁-C₃)alkyl; 4.5.j) halogen; 4.5.l) NO₂; 4.5.m) CN; or 4.5.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N; and k represents 0, 1, or 2; 4.6)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3; 4.7)

wherein n represents 1, 2, or 3; and p represents 0, 1, or 2; 4.8)

wherein q represents 1, 2, or 3; 4.9)

wherein R¹⁷⁸ represents 4.9.a) H; 4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁷⁹ in which R¹⁷⁹ represents H or (C₁-C₃)alkyl optionally substituted with halogen; 4.9.c) —(C₃-C₇)cycloalkyl which may optionally bear halogen; 4.9.d) —(C₂-C₅)alkenyl which may optionally bear halogen; 4.9.e) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally substitutued phenyl or —(C₁-C₃)alkyl, which may be substituted with halogen or —OR¹⁸¹ wherein R¹⁸¹ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.9.f) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.9.f1) halogen; 4.9.f2) optionally substituted phenyl; 4.9.f3) —S(O)₂CH₃; 4.9.f4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.9.f5) —NR¹⁸⁴R¹⁸⁵ in which R¹⁸⁴ and R¹⁸⁵ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(185a) wherein R^(185a) represents H or (C₁-C₃)alkyl, or R¹⁸⁴ and R¹⁸⁵ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁸⁶ wherein R¹⁸⁶ represents H or (C₁-C₃)alkyl; 4.9.g) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₄)alkyl; or 4.9.h) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each independently represents H or —(C₁-C₄)alkyl which may optionally bear halogen, or R¹⁸⁸ and R¹⁸⁹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁰ wherein R¹⁹⁰ represents H or (C₁-C₃)alkyl; r represents 0, 1,or2; and s represents 0 or 1; 4.10)

wherein R¹⁹¹ represents 4.10.a) H; 4.10.b) —(C₁-C₃)alkyl which may optionally bear halogen or —OR¹⁹² in which R¹⁹² represents H or (C₁-C₃)alkyl; 4.10c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or —(C₁-C₃)alkyl, both of which may be substituted with halogen or —(C₁-C₃)alkyl; 4.10.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.10.d1) halogen; 4.10.d2) phenyl; 4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; and 4.10.d5) —NR¹⁹⁶R¹⁹⁷ in which R¹⁹⁶ and R¹⁹⁷ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen or OR^(197a) wherein R^(197a) represents H or (C₁-C₃)alkyl, or R¹⁹⁶ and R¹⁹⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR¹⁹⁸ wherein R¹⁹⁸ represents H or (C₁-C₃)alkyl; 4.10.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or 4.10.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen, or R²⁰⁰ and R²⁰¹ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR²⁰² wherein R²⁰² represents H or (C₁-C₃)alkyl; and X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H or —(C₁-C₃)alkyl; and t represents 0, 1, or 2; 4.11) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.11.a) halogen; 4.11.b) optionally substituted phenyl; 4.11.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.11.d)

4.12) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O and S, said alkyl or ring optionally bearing up to 3 substituents independently selected from 4.12.a) halogen; 4.12.b) optionally substituted phenyl; 4.12.c) OR²⁰⁵ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.12.d)

4.13) halogen; or 4.14) CN; or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 1 wherein in formula (I)

wherein: X⁰ represents C or N; R¹ represents 1.1) phenyl which may optionally bear up to 4 substituents independently selected from the group consisting of 1.1.a) (C₁-C₄)alkyl, which may optionally bear up to 3 halogen substituents; 1.1.b) OR¹⁰ wherein R¹⁰ represents H; phenyl; benzyl; (C₃-C₆)cycloalkyl; or (C₁-C₄)alkyl which may optionally bear up to 3 halogen substituents; 1.1.c) halogen; and 1.1.d) —C(O)—R²⁰⁹ wherein R²⁰⁹ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; or R¹ represents 1.2) a 5-6 membered aromatic heterocycle selected from imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, and furan; said R¹ heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of 1.2.a) (C₁-C₄)alkyl, which may optionally bear up to 3 halogen substituents; 1.2.b) OR⁵⁰ wherein R⁵⁰ represents H; phenyl; benzyl; —(C₃-C₆)cycloalkyl; or —(C₁-C₄)alkyl which may optionally bear up to 3 halogen substituents; 1.2.c) halogen; and 1.2.d) —C(O)—R²¹⁰ wherein R²¹⁰ represents H or —(C₁-C₄)alkyl which may optionally bear up to 3 halogens; R² represents halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R³ represents hydrogen; halogen; —(C₁-C₅)alkyl which may optionally bear halogen; or —O(C₁-C₃)alkyl which may optionally bear halogen; R⁴ represents 4.1) —(C₁-C₅)alkyl which is optionally substituted with 4.1.a) -halogen; 4.1.b) —OR¹¹⁰ wherein R¹¹⁰ represents H or —(C₁-C₃)alkyl which may optionally bear up to 3 halogen substituents 4.1.c) —NR¹¹⁵R¹¹⁶ wherein R¹¹⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen and R¹¹⁶ represents H, optionally substituted phenyl, or —(C₁-C₅)alkyl which may optionally bear up to 3 substituents independently selected from 4.1.c1) halogen; and 4.1.c2) OR¹¹⁷ wherein R¹¹⁷ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen or —O—(C₁-C₃)alkyl; d represents 1, 2, or 3; e represents 0 or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen; g represents 1, 2, or3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents 4.4.a) H; 4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen; 4.4.c) —SO₂R¹²⁷ wherein R¹²⁷ represents optionally substituted phenyl, or —(C₁-C₃)alkyl which may optionally bear halogen; 4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents 4.4.d1) optionally substituted phenyl, 4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.4.d2.1) halogen; and 4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl; or 4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen; and j represents 1, 2, or 3; 4.5)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3; 4.6)

wherein n represents 1, 2, or 3; and p represents 0, 1, or 2; 4.7)

wherein q represents 1, 2, or 3; 4.8)

wherein R¹⁷⁸ represents 4.8.a) H; 4.8.b) —(C₁-C₃)alkyl which may optionally bear halogen; 4.8.c) —SO₂R¹⁸⁰ wherein R¹⁸⁰ represents optionally substitutued phenyl or —(C₁-C₃)alkyl, which may be substituted with halogen; 4.8.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.9.d1) halogen; and 4.9.d4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.8.e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl; or 4.8.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen; r represents 0, 1, or 2; and s represents 0 or 1; 4.9)

wherein R¹⁹¹ represents 4.9.a) H; 4.9.b) —(C₁-C₃)alkyl which may optionally bear halogen; 4.9.c) —SO₂R¹⁹³ wherein R¹⁹³ represents phenyl or —(C₁-C₃)alkyl, both of which may be substituted with halogen; 4.9.d) —C(O)R¹⁹⁴ wherein R¹⁹⁴ represents (C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.10.d1) halogen; 4.10.d2) phenyl; and 4.10.d4) OR¹⁹⁵ wherein R¹⁹⁵ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.9.e) —C(O)OR¹⁹⁹ wherein R¹⁹⁹ represents (C₁-C₃)alkyl; or 4.9.f) —C(O)—NR²⁰⁰R²⁰¹ wherein R²⁰⁰ and R²⁰¹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen; X represents O, S, S(O)₂, or NR²⁰³ wherein R²⁰³ represents H or —(C₁-C₃)alkyl; and t represents 0, 1, or 2; 4.10) —C(O)R²⁰⁴ wherein R²⁰⁴ represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.10.a) halogen; 4.10.b) optionally substituted phenyl; 4.10.c) OR²⁰⁵ wherein R²⁰⁵ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.10.d)

4.11) —C(O)—NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ each independently represents H or (C₁-C₃)alkyl, or R²⁰⁶ and R²⁰⁷ may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O and S, said alkyl or ring optionally bearing up to 3 substituents independently selected from 4.11.a) halogen; 4.11.b) optionally substituted phenyl; 4.11.c) OR²⁰⁸ wherein R²⁰⁸ represents H or —(C₁-C₃)alkyl which may optionally bear halogen; and 4.11.d)

4.12) halogen; or 4.13) CN; or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1 wherein in formula (1)

wherein: X⁰ represents C; R¹ represents 1.1) phenyl bearing 1 or 2 substituents independently selected from the group consisting of 1.1.a) methyl; 1.1.b) trifluoromethyl; and 1.1.c) halogen; 1.1.d) —C(O)(C₁-C₄)alkyl which may optionally bear up to 3 halogens; or R¹ represents 1.2) a 5-6 membered aromatic heterocycle selected from imidazole, thiazole, oxazole, pyridine, pyrazole, pyrimidine, isoxazole, isothiazole, thiophene, and furan; said R¹ heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of 1.2.a) methyl; 1.2.b) trifluoromethyl; 1.2.c) halogen; and 1.2.d) —C(O)(C₁-C₄)alkyl which may optionally bear up to 3 halogens; R² represents halogen; R³ represents hydrogen or halogen; and R⁴ represents 4.2)

wherein R¹²¹ represents —(C₁-C₃)alkyl which may optionally bear halogen or —O—(C₁-C₃)alkyl; d represents 1, 2, or 3; e represents0 or 1; f represents 0, 1, or 2; 4.3)

wherein R¹²³ represents —(C₁-C₃)alkyl which may optionally bear halogen; g represents 1, 2, or 3; h represents 0, 1, or 2; 4.4)

wherein R¹²⁵ represents 4.4.a) H; 4.4.b) —(C₁-C₃)alkyl which may optionally bear halogen; 4.4.d) —C(O)R¹²⁹ wherein R¹²⁹ represents 4.4.d1) optionally substituted phenyl, 4.4.d2) —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.4.d2.1) halogen; and 4.4.d2.4) —OR¹³⁰ wherein R¹³⁰ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.4.d3) —OR¹³⁴ wherein R¹³⁴ represents (C₁-C₃)alkyl; or 4.4.d4) NR¹³⁵R¹³⁶ wherein R¹³⁵ and R¹³⁶ are independently H or —(C₁-C₃)alkyl which may optionally bear halogen; and j represents 1, 2, or 3; 4.5)

wherein R¹⁷⁷ represents H or —(C₁-C₃)alkyl; and m represents 1, 2, or 3; 4.6)

wherein n represents 1, 2, or 3; and p represents 0, 1, or 2; 4.7)

wherein q represents 1, 2, or 3; 4.8)

wherein R¹⁷⁸ represents 4.8.a) H; 4.8.b) —(C₁-C₃)alkyl which may optionally bear halogen; 4.8.d) —C(O)R¹⁸² wherein R¹⁸² represents optionally substituted phenyl or —(C₁-C₃)alkyl which may optionally bear up to 3 substituents independently selected from 4.8.d1) halogen; and 4.8.d4) OR¹⁸³ wherein R¹⁸³ represents H or (C₁-C₃)alkyl which may optionally bear halogen; 4.8e) —C(O)OR¹⁸⁷ wherein R¹⁸⁷ represents (C₁-C₃)alkyl; or 4.8.f) —C(O)—NR¹⁸⁸R¹⁸⁹ wherein R¹⁸⁸ and R¹⁸⁹ each independently represents H or —(C₁-C₃)alkyl which may optionally bear halogen; r represents 0, 1, or 2; and s represents 0 or 1; or a pharmaceutically acceptable salt thereof.
 7. A compound having the formula: N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-tert-butylisoxazol-5-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,6-difluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-(3-tert-butylisoxazol-5-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-fluoro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[3-(trifluoromethoxy)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methoxyphenyl}-N′-[2-fluoro -5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-3-methoxyphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-tert-butyl-2-methoxyphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2,5-dimethylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-methylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-methylphenyl)urea hydrochloride; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(2-tert-butylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-ethylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-fluoropyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[5-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-methylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-3-(trifluoromethyl)phenyl]urea; N-(3-acetylphenyl)-N′-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}urea trifluoroacetate; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3,4-dimethylphenyl)urea trifluoroacetate; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3,5-dimethylphenyl)urea trifluoroacetate; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-chloro-4-methylphenyl)urea trifluoroacetate; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(5-chloropyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-chlorophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-bromophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-methoxypyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-ethylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(6-methoxypyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(6-bromopyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(3-phenoxyphenyl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-ethylphenyl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-methylphenyl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl 4-[(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate; N-{4-[4-amino-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl 4-[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)methyl]piperazine-1-carboxylate; N-[4-(4-amino-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{[4-(ethylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{[4-(isopropylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4-triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-({4-[(2,2,2-trifluoroethyl)sulfonyl]piperazin-1-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(5-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}pyridin-2-yl)-N′-[2-fluoro-5-(fluoromethyl)phenyl]urea; N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl 4-({4-amino-5-[4-({[(6-bromopyridin-2-yl)amino]carbonyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}methyl)piperazine-1-carboxylate; N-{4-[4-amino-7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea; N-(4-{4-amino-7-[(4-isopropylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-(6-bromopyridin-2-yl)urea; N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-(6-bromopyridin-2-yl)urea; N-[4-(4-amino-7-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea; N-[4-(4-amino-7-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea; 4-amino-N-(2,2,2-trifluoroethyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; 4-amino-N-(tert-butyl)-5-{4-[({[6-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea; N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-(6-bromopyridin-2-yl)urea; N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-(6-bromopyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylacetyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-hydroxy-1-methylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[6-(trifluoromethyl)pyridin-2-yl]urea; N-[4-(4-amino-7-{[(2,2,2-trifluoroethyl)amino]methyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl 4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(trifluoroacetyl)piperidin-4-yl]pyrrolo[2,1-f]E 1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2-hydroxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[7-(1-allylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; ethyl [4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]acetate; [4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]acetic acid; 2-[4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]-N-methylacetamide; N-(4-{4-amino-7-[1-(2,3-dihydroxypropyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 4-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-ethylpiperidine-1-carboxamide; 4-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-tert-butylpiperidine-1-carboxamide; 4-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-isopropylpiperidine-1-carboxamide; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-bromophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-chlorophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-methoxyphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(4-methylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(3-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3-chlorophenyl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(4-tert-butylpyrdin-2-yl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(4-methylpyridin-2-yl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(3,4-dichlorophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-chlorophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluoro-5-methylphenyl}-N′-(3-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3,4-dichlorophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-tert-butylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(3-ethylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-ethylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[4-chloro-3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3,4-dichlorophenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3,5-dimethylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5yl}-2-methylphenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-fluoro-3-methylphenyl)urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-ethylphenyl)urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; 1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-3-(2-fluoro-5-methylphenyl)urea; 1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-(2-fluoro-5-methylphenyl)urea; N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,5-difluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-pyrrolidin-1-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[3-(4-methylpiperazin-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{7-[3-(4-acetylpiperazin-1-yl)propyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; 1-{4-[4-amino-7-(3-hydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[3-(1,4-oxazepan-4-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[3-(dimethylamino)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[3-(3-oxopiperazin-1-yl)propyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-thiomorpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{3-[ethyl(2-hydroxyethyl)amino]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl 3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate; tert-butyl 3-{4-amino-5-[4-({([2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate; 1-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-(4-{4-amino-7-[1-(methylsulfonyl)pyrrolidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 3-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N,N-dimethylpyrrolidine-1-carboxamide; 1-{4-[4-amino-7-(1-glycoloylpyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea; 1-[4-(4-amino-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl 3-{4-amino-5-[3-fluoro-4-({[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}pyrrolidine-1-carboxylate; 4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-methylpiperidine-1-carboxamide; 4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N,N-dimethylpiperidine-1-carboxamide; N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[2-(dimethylamino)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[2-(4-methylpiperazin-1-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{2-[2-(methoxymethyl)pyrrolidin-1-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(2-pyrrolidin-1-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(2-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(4-morpholin-4-ylbutyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[2-(1,4-oxazepan-4-yl)ethyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(1-lactoylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(cyclopropylcarbonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(morpholin-4-ylacetyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-glycoloylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[1-(cyclopropylcarbonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[1-(N,N-dimethylglycyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2-ethoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2-ethoxyethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 4-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethylpiperidine-1-carboxamide; N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4-triazin-5-yl]phenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(1-hydroxyprop-2-en-1-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-hydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,2-dihydroxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,2,3-trihydroxypropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 2-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-oxoethyl acetate; N-{4-[4-amino-7-(bromoacetyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(3-morpholin-4-ylpropoxy)acetyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(7-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(2-morpholin-4-ylethoxy)acetyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[1-(2,2-difluoroethyl)piperidin-4-yl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-chlorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-cyclopropylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; tert-butyl-4-(4-amino-5-{3-chloro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-chlorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-(trifluoromethyl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea; tert-butyl-4-(4-amino-5-{3-fluoro-4-[({4-[(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; tert-butyl-4-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; N-{4-[4-amino-7-(1,3-oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; tert-butyl-4-(4-amino-5-{2,5-difluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenylamino]carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate; N-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2,5-difluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-(trifluoromethoxy)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-(4-tert-butylpyridin-2-yl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[3-(trifluoromethyl)phenyl]urea; tert-butyl-2-({[(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]amino}methyl)morpholine-4-carboxylate; 4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-[4-(4-amino-7-{[2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-2-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}phenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea; 4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; 4-amino-5-{3-fluoro-4-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; 4-amino-5-{4-[({[2-chloro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; 4-amino-5-{2,5-difluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}-N-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxamide; 1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(4-methylpiperazin-1-yl)carbonyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; 1-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-3-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-2-ylcarbonyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; or a pharmaceutically acceptable salt thereof
 8. The compound of claim 7 having the formula: N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{5-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]pyridin-2-yl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methylphenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-chloro-5-(trifluoromethyl)phenyl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-(4-{7-[(4-acetylpiperazin-1-yl)methyl]-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; [4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]acetic acid; 2-[4-(4-amino-5-{3-fluoro-4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidin-1-yl]-N-methylacetamide; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[3-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(1,1-dioxidothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(2-fluoro-5-methylphenyl)urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2-fluorophenyl)-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-(4-{4-amino-7-[(3-oxopiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-5-yl}-2,5-difluorophenyl)-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-chlorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-(4-fluoro-3-methylphenyl)urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-[4-(4-amino-7-{3-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]propyl}pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; 1-{4-[4-amino-7-(1-glycoloylpyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea; 1-{4-[7-(1-acetylpyrrolidin-3-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[4-(trifluoromethyl)pyridin-2-yl]urea; 4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-methylpiperidine-1-carboxamide; N-{4-[4-amino-7-(2-morpholin-4-ylethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2,5-difluorophenyl}-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea; N-{4-[4-amino-7-(1-glycoloylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[7-(1-acetylpiperidin-4-yl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[4-(trifluoromethyl)pyridin-2-yl]urea; N-{4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-N′-[1-oxido-4-(trifluoromethyl)pyridin-2-yl]urea; or a pharmaceutically acceptable salt thereof.
 9. A pharmaceutical composition comprising a compound as defined in claim 1, plus a pharmaceutically acceptable carrier.
 10. A method of inhibiting FGFR-1 in a cell comprising contacting a cell containing FGFR-1 with a compound as defined in claim
 1. 11. A method of inhibiting tumor proliferation in a mammal, comprising administering to said mammal an effective amount of a compound as defined in claim
 1. 12. A method of treating cancer in a mammal, comprising administering to said mammal an effective amount of a compound as defined in claim
 1. 13. The method of claim 12 wherein said mammal is a human. 